The DOI matches its Crossref record; 50 of the 51 references it cites were found in a registry or an index; none of the 39 sources its claims cite is checked for support yet.
A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis
Open accessAbstract
Metastasis and chemoresistance in cancer are linked phenomena but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b+Gr1+ myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. While chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α heightens the expression of CXCL1/2 in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.
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57 Own result · 35 Own interpretation · 24 Not checked yet · 3 Own method · 1 No basis given
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“Knockdown of CXCL1 and 2 using two independent shRNA hairpins (Figure S1C–D) significantly reduced mammary tumor growth in all three models (Figures 1C–D, 1G–H and S1E–F)”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
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“A significant reduction in CD11b+Gr1+ myeloid cells was observed in CXCL1/2 knockdown tumors in both models (Figure S2G–H).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
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“This decrease was associated with reduced metastasis in the lungs (Figures 1E–F, 1I–J and S1G).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
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“Indeed, CXCL1 and CXCL2 showed a similar expression pattern in a combined cohort of 615 primary breast cancers (Figure 1A).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
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“Fluorescence in situ hybridization (FISH) of human tissue samples showed that CXCL1 and CXCL2 were amplified in 7.5% of primary breast tumors and in 19.9% of metastases (Figures 1B and S1A).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
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“LM2 cells showed upregulation of CXCL1/2 compared to the parental line (Figure S1B).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
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“Furthermore, lung colonization assays by tail vein injection of LM2 cells confirmed that the effect of CXCL1/2 depletion on metastasis is not solely a consequence of decreased tumor burden (Figure 1K–N).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
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“Compared to the high levels of CXCL1/2 expression in lung metastatic cell lines, the expression of CXCR1, CXCR2 and DARC was negligibly low both at the RNA and protein levels (Figure 2C and Figure S2F and (Muller et al., 2001)).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
What the sources say
- Not checked yetcites Muller et al., 2001 source
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“Detailed characterization of the myeloid cells showed a decrease in the CD11b+Ly6G+ granulocytic MDSC population in CXCL1/2 knockdown tumors compared to controls (Figure 2D and S2I).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
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“Reduction in CXCL1/2 levels in the LM2 xenograft and PyMT transplantation models was associated with a significant increase in apoptosis in the tumors (Figure 2A–B).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
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“Similar results were obtained upon size-matching the knockdown tumors to controls (Figure S1H and I).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
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“Similar analysis of a dataset generated from 67 metastases from breast cancer patients showed a 61% overlap in CXCL1-associated genes between primary breast tumors and metastases (Figure 3B; Tables S3, S4).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
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“Among a panel of prototypical activators of the NFκB/STAT1 pathway that we assayed by qRT-PCR, TNF-α was strikingly induced in endothelial cells upon doxorubicin chemotherapy treatment (Figure 6B).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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“In addition to CXCL1/2 and S100A8/9, the CXCL1-associated chemokine genes CCL20 and CXCL3 were also highly expressed in response to chemotherapy (Figure S5B).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > The CXCL1/2–S100A8/9 Survival Axis Is Hyperactivated by Chemotherapy
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“However, LM2 tumor cells incubated with conditioned media from chemotherapy-treated primary endothelial cells or primary bone marrow-derived cells showed a significant increase in CXCL1/2 expression (Figures 6A and S6B).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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In the paper
“Consistent with our experimental models, a significant increase in S100A9 expressing cells was observed in breast cancers after chemotherapy treatment (Figure 5G–H and Table S5).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 association with resistance to perioperative chemotherapy
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“Although induction of CXCL chemokines occurs during chemotherapy-induced senescence (Coppe et al., 2008), there was no discernible increase in senescence in LM2 tumors upon AC chemotherapy treatment (Figure S5C–D).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > The CXCL1/2–S100A8/9 Survival Axis Is Hyperactivated by Chemotherapy
What the sources say
- Not checked yetcites Coppe et al., 2008 source
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“Furthermore, the enforced expression of S100A8/9 in LM2 cells (Figure S3G–H) rescued the CXCL1/2 knockdown phenotype of reduced tumor growth and metastasis (Figures 3H,I and S3I).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
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“Treatment with anti-TNF-α antibody infliximab reduced recruitment of S100A9-expressing cells in chemotherapy-treated mammary tumors (Figure 6G–H).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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In the paper
“Importantly, histopathological analysis revealed that cells from the tumor microenvironment specifically lymphatic and blood vessels and fibroblast-rich stroma showed strong TNF-α staining after chemotherapy (Figure 6J and S6D).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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“Compared to the myeloid components, lymphocytic cells represented a minority of leukocytes infiltrated in the immunocompetent PyMT transplanted tumors (Table S1).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
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“Consistent with our hypothesis, a significant increase in TNF-α immunostaining was observed in patient samples after neoadjuvant AC chemotherapy treatment (Figure 6I–K)”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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“TNF-α induction in response to chemotherapy also occurred in smooth muscle and bone marrow derived cells (Figure 6E)”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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“Moreover, we observed a ten-fold increase in TNF-α expression in purified lung endothelial cells from LM2 tumor bearing mice systemically treated with AC chemotherapy (Figure 6C,D).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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“The requirement of S100A8/9 in cell survival was even more evident when tumor-bearing mice were treated with chemotherapeutic agents as an inducer of cell death (Figure 4B–C and S4A).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
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“In our experimental models, enhanced expression of CXCL1/2 in response to chemotherapy was not due to additional amplification of the locus as determined by FISH analysis (Figure S6A).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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“CXCL1/2 upregulation in the LM2 tumors was but was also observed with another commonly used chemotherapeutic agent, paclitaxel (Figure S5A).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > The CXCL1/2–S100A8/9 Survival Axis Is Hyperactivated by Chemotherapy
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“However, after subsequent rounds of chemotherapy, tumors became refractory as evidenced by reduction in apoptosis and resumed tumor growth (Figure 5A–B).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > The CXCL1/2–S100A8/9 Survival Axis Is Hyperactivated by Chemotherapy
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“These genes showed a predominance of chemokines (40%) and cytokines (21%).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
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In the paper
“Tumor-bearing mice transplanted with S100A9−/− bone marrow showed a marked increase in the number of apoptotic cells in the mammary tumors and the lung (Figure 4A).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
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“Similar numbers of CD11b+ and CD68+ myeloid cells were present in tumors and lung nodules from mice transplanted with either S100A9−/− or S100A9+/+ bone marrow cells (Figure S4B and data not shown).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
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“Analysis of 615 breast tumors from three independent datasets yielded 43 such genes that correlated with CXCL1 with a coefficient >0.3 (Figure 3A and Table S3).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
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“Direct treatment of LM2 cells with the chemotherapeutic agents did not induce CXCL1/2 expression (Figure S6B and data not shown).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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“Consistent with the survival advantage provided by S100A8/9 in vivo, co-culture of cancer cells with bone marrow derived CD11b+Gr1+ cells protected cancer cells from doxorubicin-induced apoptosis (Figure 4D).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
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“NFκB activation by TNF-α stimulated the expression of CXCL1/2 in LM2 tumor cells, as determined with the use of NFκB pathway inhibitor (Nemo binding domain peptide or NBD) (Figure 6F).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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In the paper
“and in LM2 mammary tumors in mice treated with AC chemotherapy (Figure S6C).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
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“Kaplan Meier analysis showed that patients with high S100A8/9 in the metastatic nodules had a significantly shorter overall survival compared to low S100A8/9 (p-value=0.01) (Figure 3K).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
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In the paper
“Mammary tumor growth and lung metastasis were significantly reduced in mice transplanted with S100a9−/− bone marrow compared to the S100a9+/+ counterpart (Figure 3E–G).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
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“Using blot arrays that detect phosphorylation of 46 different protein kinases, we found that S100A8/9 cause activation of ERK1/2, p38 MAPK, and p70S6K in LM2 cells (Figures 4E and S4D), as confirmed by immunoblotting (Figures S4E–F).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
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“As a single agent CXCR2 inhibitor had partial to no effect depending on the model system.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Blocking CXCL1 Signaling Increases the Effectiveness of Chemotherapy
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In the paper
“Tumor-bearing mice treated with AC chemotherapy alone showed a reduction in tumor growth (Figures 7A,B and S7A,B).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Blocking CXCL1 Signaling Increases the Effectiveness of Chemotherapy
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In the paper
“In addition to activating MAPK pathways (Gebhardt et al., 2006; Ichikawa et al., 2011), we find that S100A8/9 activate p70S6K as contributors to the pro-survival effect of S100A8/9 in these cells.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Clinically as well as biologically, metastasis is intricately linked with resistance to chemotherapy (Hu et al., 2009; Morris et al., 2009).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > INTRODUCTION
What the sources say
- Not checked yetcites Hu et al., 2009
- Not checked yetcites Morris et al., 2009 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These results suggested that increased copy number contributes to the higher CXCL1/2 expression in invasive breast tumors and metastases.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“We uncovered a network of paracrine signals between carcinoma, myeloid and endothelial cells that drives both processes in breast cancer.”
- Also stated in: § INTRODUCTION · plain
“We uncovered a paracrine network, with the chemokines CXCL1 and 2 at its core that mediates lung metastasis and chemoresistance in breast cancer.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § INTRODUCTION · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We concluded that CXCL1/2 play a prominent role in breast cancer progression and metastasis.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that the ERK1/2 and p70S6K signaling mediate the pro-survival effect of S100A8/9 in metastatic cells.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
hedgeddirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After confirming successful engraftment of S100a9+/+ or S100a9−/− bonemarrow with an efficiency of >98% (Figure S3C)”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Our findings suggest that a self-defeating consequence of at least some chemotherapy drugs is the release of potent pro-inflammatory cytokines such as TNF-α from stromal sources.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Blocking CXCL1 Signaling Increases the Effectiveness of Chemotherapy
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“This result ruled out the possibility that higher apoptotic rates in the S100A9−/− group were due to a defective accumulation of myeloid cells (Hiratsuka et al., 2008).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
What the sources say
- Not checked yetcites Hiratsuka et al., 2008 source
boosted- Asserted: passes — The authors put it forward as true.
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In the paper
“Together, these results suggest that S100A8/9 mediate the pro-metastatic effect of CXCL1/2 in our models.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Together, these results suggest that chemotherapy activates a burst of paracrine factors including the cancer cell survival axis CXCL1/2-S100A8/9 that selects for cancer cells that can resist chemotherapy.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > The CXCL1/2–S100A8/9 Survival Axis Is Hyperactivated by Chemotherapy
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that TNF-α release is a general response to chemotherapy in different stromal cell types.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, TNF-α from chemotherapy-activated stroma can boost the CXCL1/2-S100A8/9 loop.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sca1, a marker of the hematopoietic stem cells, was expressed in CD11b+Ly6G+ populations, indicating potential progenitor-like phenotype of the tumor granulocytic cells recruited by CXCL1/2 (Table S2).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“CXCL1/2 are target genes of the NFκB/STAT1 pathway (Amiri and Richmond, 2003).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Chemotherapy Induces TNF-α to Boost the CXCL1/2–S100A8/9 Axis
What the sources say
- Not checked yetcites Amiri and Richmond, 2003
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In line with our findings, recent Phase 2 study in breast cancer patients showed that non-responders of neoadjuvant chemotherapy and patients with residual disease had significantly higher circulating MDSC levels than did responders (Montero et al., 2011).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
What the sources say
- Not checked yetcites Montero et al., 2011
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Such a paracrine survival network could be beneficial to cancer cells under stress both in the primary tumor and at distant metastatic sites.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our study delineates a new role for the CD11b+Gr1+ cells in mediating metastatic breast cancer cell survival through the production of S100A8/9.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addressing this challenge, our work links CXCL1/2 and S100A8/9 as functional partners of a paracrine loop between breast cancer cells and CD11b+Gr1+ myeloid cells that supports the survival of cancer cells facing the rigors of invading new microenvironments or the impact of chemotherapy (Figure 7E).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The present work sheds light on how the tumor microenvironment responds to chemotherapy with hyperactivation of a TNF-α-CXCL1/2-S100A8/9 paracrine axis for cancer cell survival under stress.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results highlight the potential of targeting the CXCL1/2-S100A8/9 axis thereby sensitizing distant metastases to standard of care chemotherapy.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Blocking CXCL1 Signaling Increases the Effectiveness of Chemotherapy
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: CXCR2 is the primary receptor for CXCL1/2.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our findings functionally unify three important inflammatory modulators, TNF-α, CXCL1/2 and S100A8/9, in a tumor-stroma paracrine axis that provides a survival advantage to metastatic cells in stressed primary and metastatic microenvironments.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, the important role of CXCR2 in pancreatic adenocarcinoma models (Ijichi et al., 2011) and of S100A8/9 in colorectal cancer (Ichikawa et al., 2011) suggest that the relevance of targeting the CXCL1/2–S100A8/9 axis may extend beyond breast cancer.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our current findings suggest that this cytokine burst includes TNF-α induced in several components of the tumor microenvironment after chemotherapy treatment.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In conclusion, our results provide mechanistic insights into the link between two major hurdles in treating breast cancer: chemoresistance and metastasis.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An adverse cycle involving TNF-α-CXCL1/2-S100A8/9 could thus be expanded in response to chemotherapy.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and we show that these agents are a promising pharmacological approach in metastatic breast cancer when combined with standard chemotherapeutic regimen.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: CXCR2 is the primary receptor for CXCL1/2.
- Rests on an assumption: Stroma has lower selective pressure for mutations and epigenetic changes than cancer cell genomes.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An undesirable consequence of the stromal TNF-α is to further boost CXCL1/2 expression in breast cancer cells.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A higher level of CXCL1/2 then drives the paracrine loop involving myeloid cell-derived S100A8/9 to enhance cancer cell survival (Figure 7E).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The effective combination of chemotherapy with CXCR2 inhibitors at the metastatic site in our preclinical models underscores the potential application of this therapy to limit disseminated tumor burden.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: CXCR2 is the primary receptor for CXCL1/2.
- Rests on an assumption: Stroma has lower selective pressure for mutations and epigenetic changes than cancer cell genomes.
- It may state two separate claims as one. 38
- Probably not a substantial claim. 13
- The quote only partly states this claim. 1
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, among other CXCR2 ligands that we tested, CXCL3 knockdown in LM2 cells contributed to tumor growth but not metastasis (Figure S1K–M).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No appreciable decrease was observed in the CD11b+Ly6C+, F4/80+ macrophages, SMA+ myofibroblast, Ter119+ erythroid cells or endothelial cells in the CXCL1/2 depleted tumors (Figure S2J–P, Table S1 and data not shown).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PyMT-F and LM2 cells grew aggressively in the mammary fat pad and metastasized to the lungs.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, CXCL1/2 knockdown was not accompanied by any visible changes in apoptosis in vitro or in angiogenesis and cell proliferation rates in tumors (Figure S2A–E).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“S100A8/9 addition only weakly activated NFκB in LM2 breast cancer cells and we detected no activation of the Akt or STAT3 pathways (Figure S4C and data not shown).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Addition of an ERK1/2 inhibitor (FR180204) or a p70S6K inhibitor (PF4708671) abolished the chemo-protective effect of S100A8/9 whereas addition of a p38 inhibitor (SB203580) showed partial effect (Figure 4F), suggesting that the ERK1/2 and p70S6K signaling mediate the pro-survival effect of S100A8/9 in metastatic cells.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“AC treated tumors significantly upregulated CXCL1/2 expression (Figure 5C–D) and this effect was associated with increased recruitment of S100A9-expressing cells (Figure 5E) and CD11b+Ly6G+ granulocytic cells (Figure 5F).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > The CXCL1/2–S100A8/9 Survival Axis Is Hyperactivated by Chemotherapy
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within the recruited CD11b+Ly6G+ population in the PyMT immunocompetent transplant tumors, 6, 12 and 25% of the cells expressed CD80, F4/80 and Sca1, respectively, and a minority expressed CD86, CD117, IL4Rα, VEGFR1 and CD34 (Table S2).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Chemotherapy treatment of mice bearing LM2 tumors initially resulted in significant apoptosis and a concomitant delay in tumor growth (Figure 5A–B).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > The CXCL1/2–S100A8/9 Survival Axis Is Hyperactivated by Chemotherapy
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CXCL1/2 depleted tumors showed a decrease in CD4+ and CD8+ lymphocytes, no major change in γδ-TCR+ and CD25+ T-regulatory cells, and moderate increases in B220+ lymphocyte and CD49b+ NK cell numbers (Table S1).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Coinjection of wild-type MPRO cells with LM2 cancer cells enhanced mammary tumor growth and lung metastasis, an effect that was significantly blunted by S100a8/9 knockdown in the MPRO cells (Figure S3E–F).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, a reduction both in monocytic CD11b+Ly6C+ and granulocytic CD11b+Ly6G+ cells occurred in the lungs of mice bearing CXCL1/2 depleted tumors with minimal changes in the number of F4/80+ macrophages (Figure S2R–T).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, this protection was more limited in co-culture with CD11b+Gr1+ cells derived from S100A9−/− marrow (Figure 4D), confirming that the pro-survival properties of myeloid factors under stress chemotherapy conditions are partly due to S100A8/9.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 Promotes Breast Cancer Cell Survival Under Chemotherapy
plainconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In contrast, Fascin that is part of a lung metastasis gene signature (Minn et al., 2005) did not show the same trend upon chemotherapy treatment as S100A8/9 (Figure S5E), further confirming the specificity of the association of S100A8/9 with chemotherapy resistance.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > S100A8/9 association with resistance to perioperative chemotherapy
What the sources say
- Not checked yetcites Minn et al., 2005 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“To identify cancer cell survival factors derived from the recruited myeloid cells, we identified candidates that are abundantly expressed in tumor-derived CD11b+Gr1+ cells and are not of epithelial origin (Figure 3C,D and Figure S3A). S100A8 and A9 fulfilled these criteria.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In line with our hypothesis, CD11b+Gr1+ cells and specifically the CD11b+Ly6G+ subpopulation expressed CXCR2 (Figure 2E, S2Q).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, when AC was combined with the CXCR2 inhibitor, lung metastatic burden was markedly reduced and the interaction between the drugs exhibited synergism (Figure 7C,D).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Blocking CXCL1 Signaling Increases the Effectiveness of Chemotherapy
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However metastatic cells were not completely eliminated and micrometastases were detected throughout the lungs (Figure 7C,D).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Blocking CXCL1 Signaling Increases the Effectiveness of Chemotherapy
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Biologically, less than 0.1% of the circulating cancer cells are estimated to withstand the harsh stresses of infiltrating and colonizing distant metastatic sites (Weiss, 2000).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > INTRODUCTION
What the sources say
- Not checked yetcites Weiss, 2000
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Drug resistance in cancer can be cell-intrinsic (Poulikakos and Rosen, 2011) or a combination of host and tumor mediated pathways (Bergers and Hanahan, 2008; Ebos et al., 2009).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > INTRODUCTION
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“CXCL1 emerged among a set of genes whose expression is associated with lung relapse in breast tumors, including tumors that had not been exposed to prior chemotherapy (Minn et al., 2007; Minn et al., 2005), and as a gene that increases the aggressiveness of circulating breast tumor cells (Kim et al., 2009).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Additionally, high expression of CXCL1 in breast tumors without gene amplification is also possible (Bieche et al., 2007).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
What the sources say
- Not checked yetcites Bieche et al., 2007 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on these results, we postulated that CXCL1/2 mediates tumor cell survival via paracrine mechanisms.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CXCL1/2 attract CD11b+Gr1+ myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CXCL1 and 2 are 90% identical by amino-acid sequence and signal through the same receptor CXCR2 (Balkwill, 2004).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
What the sources say
- Not checked yetcites Balkwill, 2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TNF-α heightens the expression of CXCL1/2 in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent evidence points to tumor microenvironment components as potential participants in the generation of chemoresistance (Denardo et al., 2011; Gilbert and Hemann, 2010; Roodhart et al., 2011; Shaked et al., 2008; Shree et al., 2011).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > INTRODUCTION
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Copy number alterations at 4q21 occur in breast cancer (Beroukhim et al., 2010) and engulf fifteen genes in the amplification peak, including CXCL1-8.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Mediate Mammary Tumor Growth and Lung Metastasis
What the sources say
- Not checked yetcites Beroukhim et al., 2010 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CXCR2 receptor is expressed by several stromal cell types such as endothelial and myeloid cells (Murdoch et al., 2008).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Recruit Myeloid Cells to Mammary Tumors
What the sources say
- Not checked yetcites Murdoch et al., 2008 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Both TLR4 and RAGE are expressed in breast cancer cells (Bos et al., 2009; Hsieh et al., 2003).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“S100A8/9 bind to Toll-like receptor 4 (TLR4) and RAGE (receptor for advanced glycation end products), which activate diverse signaling cascades (Gebhardt et al., 2006; Vogl et al., 2007).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“S100A8/9 are low molecular weight calcium-binding proteins that are associated with chronic inflammation and cancer (Gebhardt et al., 2006).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
What the sources say
- Not checked yetcites Gebhardt et al., 2006 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively our results suggest that CXCL1/2 from breast cancer cells recruit myeloid producers of S100A8/9, which in turn promote breast cancer metastasis.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > CXCL1/2 Promote Metastasis Through Myeloid Cell-derived S100A8/9
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Once initiated, this chemo-protective program could become self-sustaining, leading to the enrichment of residual aggressive clones able to resist chemotherapy and thrive in the lung”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This raises the possibility of clinically targeting this axis both to limit the dissemination of cancer cells and to diminish drug resistance.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Such pro-inflammatory bursts can boost the CXCL1/2-S100A8/9 survival axis and facilitates the expansion of chemoresistant breast cancer cells.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > RESULTS > Blocking CXCL1 Signaling Increases the Effectiveness of Chemotherapy
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“CD11b+Gr1+ myeloid cells are a heterogeneous group with previously identified roles in tumor angiogenesis and T cell immunosuppression (Gabrilovich and Nagaraj, 2009; Ostrand-Rosenberg and Sinha, 2009; Shojaei et al., 2007).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our findings argue that although therapy induced inflammation is a predominant feature of the use of chemotherapy, disrupting the CXCL1 driven paracrine axis could improve therapeutic response in existing lesions and also suppress metastasis, even at an advanced stage of tumor progression.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Stroma has lower selective pressure for mutations and epigenetic changes than cancer cell genomes.
In the paper
“The major impediments to cure advanced breast cancer are the emergence of pan-resistance to all known chemotherapy drugs and the development of widely metastatic disease, two phenomena that are closely linked clinically (Gonzalez-Angulo et al., 2007).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
What the sources say
- Not checked yetcites Gonzalez-Angulo et al., 2007 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The critical role of the microenvironment in tumor progression and response to therapy is being increasingly recognized (Condeelis and Pollard, 2006; Denardo et al., 2011; Gilbert and Hemann, 2010; Shree et al., 2011; Tan et al., 2011).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent reports (Denardo et al., 2011; Gilbert and Hemann, 2010) and the present work show that chemotherapy induces a storm of cytokines and chemokines in the tumor microenvironment many of which might be linked to chemoresistance.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > A Three-Way Paracrine Axis Underlying Chemoresistance and Metastasis
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“CXCR2 receptor antagonists are in clinical trials for chronic inflammatory diseases (Chapman et al., 2009)”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
What the sources say
- Not checked yetcites Chapman et al., 2009 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings accentuate the clinical relevance of CD11b+Gr1+ in rendering chemotherapy ineffective and promoting metastasis.”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > DISCUSSION > Biological and Clinical Implications
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All experiments using animals were done in accordance to a protocol approved by MSKCC Institutional Animal Care and Use Committee (IACUC).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > EXPERIMENTAL PROCEDURES > Animal studies
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Paraffin embedded tissue microarrays and sections from lung metastases and primary breast tumor cores before and after chemotherapy treatment were acquired from the MSKCC Department of Pathology in compliance with protocols approved by the MSKCC Institutional Review Board (IRB).”
§ A CXCL1 paracrine network links cancer chemoresistance and metastasis > EXPERIMENTAL PROCEDURES > Patient samples
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
An integrated understanding of acquired drug resistance in the context of inputs from tumor and its microenvironment is lacking.
“However, an integrated understanding of acquired drug resistance in the context of inputs from tumor and its microenvironment is lacking.”
The paper relies on this without support.
A very small fraction of cells exposed to genotoxic stress can survive and outgrow under repeated cycles of chemotherapy.
“Similarly, a very small fraction of cells exposed to genotoxic stress can survive and outgrow under repeated cycles of chemotherapy.”
The paper relies on this without support.
CXCR2 is the primary receptor for CXCL1/2.
“we utilized antagonists of CXCR2, the primary receptor for CXCL1/2”
The paper relies on this without support.
Stroma has lower selective pressure for mutations and epigenetic changes than cancer cell genomes.
“targeting the immune microenvironment would be an attractive option because of the potentially low selective pressure for mutations and epigenetic changes on the stroma compared to the cancer cell genomes.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Notably, data from various mouse models indicate that disrupting the CXCR1/2–MDSC axis in tumours is therapeutically efficacious across a wide variety of solid cancers166–172.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [166]
Citations
Cites
Myeloid-derived-suppressor cells as regulators of the immune system
Gabrilovich, D. I., & Nagaraj, S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2506 · Cited by 6,753
Involvement of chemokine receptors in breast cancer metastasis
Müller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S. N., et al. (2001) · Nature · doi:10.1038/35065016 · Cited by 5,340
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017
Modes of resistance to anti-angiogenic therapy
Bergers, G., & Hanahan, D. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2442 · Cited by 2,953 · cited 2×
“Drug resistance in cancer can be cell-intrinsic (Poulikakos and Rosen, 2011) or a combination of host and tumor mediated pathways (Bergers and Hanahan, 2008; Ebos et al., 2009).”
Genes that mediate breast cancer metastasis to lung
Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., Viale, A., Olshen, A. B., Gerald, W. L., & Massagué, J. (2005) · Nature · doi:10.1038/nature03799 · Cited by 2,922
Self-citationGene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer
Wang, Y., Klijn, J. G. M., Zhang, Y., Sieuwerts, A. M., Look, M. P., Yang, F., Talantov, D., Timmermans, M. A. M., Gelder, M. E. M., Yu, J. X., et al. (2005) · The Lancet · doi:10.1016/s0140-6736(05)17947-1 · Cited by 2,831
Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis
Condeelis, J. S., & Pollard, J. W. (2006) · Cell · doi:10.1016/j.cell.2006.01.007 · Cited by 2,677
Cancer and the chemokine network
Balkwill, F. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1388 · Cited by 2,343
Endogenous human microRNAs that suppress breast cancer metastasis
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Self-citationGenes that mediate breast cancer metastasis to the brain
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Metadata
- Authors
- Acharyya, S., Oskarsson, T., Vanharanta, S., Malladi, S., Kim, J., Morris, P. G., Manova-Todorova, K., Leversha, M., Hogg, N., Seshan, V. E., Norton, L., Brogi, E., & Massagué, J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cancer Research UK (GB)
- Corresponding author
- Massagué, Joan
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 150
- Issue
- 1
- Pages
- 165-178
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3528019
- OpenAlex
- W2151832198
- Semantic Scholar
- 925990be27c66128df282d0f18c8f2ac8b6b6953
- Cited by
- 1,085
- References
- 51
- Citations by year
- 2026: 32 · 2025: 45 · 2024: 81 · 2023: 81 · 2022: 81 · 2021: 139 · 2020: 99 · 2019: 68 · 2018: 71 · 2017: 75 · 2016: 77 · 2015: 78 · 2014: 69 · 2013: 77 · 2012: 12
- FWCI
- 37.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (R37CA034610, P01CA094060, U54CA163167, CA94060, P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- CXCL1, CXCL2, chemoresistance, metastasis, breast cancer, paracrine signaling, myeloid cells, endothelial cells, S100A8/S100A9, TNF-α, NF-kB, CXCR2, tumor microenvironment, chemotherapy
- MeSH terms
- Animals, Breast Neoplasms, Carcinoma, Disease Models, Animal, Female, Humans, Lung Neoplasms, Lymph Nodes, Lymphatic Metastasis, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasm Transplantation, Transplantation, Heterologous, Drug Resistance, Neoplasm, Paracrine Communication, Myeloid Cells, Calgranulin A, Calgranulin B, Endothelial Cells, Mice, Chemokine CXCL1, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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