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Cited by 168Mesenchymal stem cell researchCancer Cells and MetastasisPeriodontal Regeneration and Treatments

Mesenchymal stem cell secretome and regenerative therapy after cancer

Open access
Zimmerlin, Ludovic, Park, Tea Soon, Zambidis, Elias T., Donnenberg, Vera S., Donnenberg, Albert D.·2013·Biochimie
DOI 10.1016/j.biochi.2013.05.010PMC PMC3825748
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Abstract

Cancer treatment generally relies on tumor ablative techniques that can lead to major functional or disfiguring defects. These post-therapy impairments require the development of safe regenerative therapy strategies during cancer remission. Many current tissue repair approaches exploit paracrine (immunomodulatory, pro-angiogenic, anti-apoptotic and pro-survival effects) or restoring (functional or structural tissue repair) properties of mesenchymal stem/stromal cells (MSC). Yet, a major concern in the application of regenerative therapies during cancer remission remains the possible triggering of cancer recurrence. Tumor relapse implies the persistence of rare subsets of tumor-initiating cancer cells which can escape anti-cancer therapies and lie dormant in specific niches awaiting reactivation via unknown stimuli. Many of the components required for successful regenerative therapy (revascularization, immunosuppression, cellular homing, tissue growth promotion) are also critical for tumor progression and metastasis. While bi-directional crosstalk between tumorigenic cells (especially aggressive cancer cell lines) and MSC (including tumor stroma-resident populations) has been demonstrated in a variety of cancers, the effects of local or systemic MSC delivery for regenerative purposes on persisting cancer cells during remission remain controversial. Both pro- and anti-tumorigenic effects of MSC have been reported in the literature. Our own data using breast cancer clinical isolates have suggested that dormant-like tumor-initiating cells do not respond to MSC signals, unlike actively dividing cancer cells which benefited from the presence of supportive MSC. The secretome of MSC isolated from various tissues may partially diverge, but it includes a core of cytokines (i.e. CCL2, CCL5, IL-6, TGFβ, VEGF), which have been implicated in tumor growth and/or metastasis. This article reviews published models for studying interactions between MSC and cancer cells with a focus on the impact of MSC secretome on cancer cell activity, and discusses the implications for regenerative therapy after cancer.

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Crossref · 10.1016/j.biochi.2013.05.010

Cites

174 of 174 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

42 of 86 cited sources checked · 8 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Both bone marrow-derived and adipose-derived MSC show tumor tropism driven by various tumor-released chemotactic factors, including CCL25, CXCL1, EGF, HDGF, IL-8, PDGF, SDF1, TGFβ and VEGF.

    “Both BM- and adipose-derived MSC display tumor tropism due to various tumor-released chemotactic factors including CCL25 [43], C-X-C motif chemokine-1 (CXCL1) [54], epidermal growth factor (EGF) [83, 84], hepatoma-derived growth factor (HDGF) [85], IL-8 [54], platelet-derived growth factor (PDGF) [84], stromal cell-derived factor-1 (SDF1, a.k.a. CXCL12) [86, 87], TGFβ [88], and VEGF [84].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [43] Xu, 2012, Bone marrow-derived mesenchymal stromal cells are attracted by multiple myeloma cell-produced chemokine CCL25 and favor myeloma cell growth in vitro and in vivo, Stem Cells source
    • cites [54] Klopp, 2012, Omental adipose tissue-derived stromal cells promote vascularization and growth of endometrial tumors, Clin. Cancer Res. source

      Citation [54] is attached to CXCL1 and IL-8, not to the other listed factors. In Results, the paper reports that both are secreted by Hec1a tumor cells and that bone marrow-derived MSC and omental adipose stromal cells migrate in response to tumor-conditioned medium. It says CXCL1 and IL-8 may trigger chemotaxis, rather than establishing that either factor drives tumor tropism. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [83] Iivanainen, 2009, The EGFR inhibitor gefitinib suppresses recruitment of pericytes and bone marrow-derived perivascular cells into tumor vessels, Microvasc. Res. source
    • cites [84] Beckermann, 2008, VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma, Br. J. Cancer source

      The Results section (“Specific migration of MSC to PDGF, EGF, and VEGF”) reports migration toward all three factors, which are the factors specifically cited to this paper. But the Methods section (“Isolation and culture of human BM-derived MSC”) says the tested MSC came from bone marrow; the paper does not establish the same response for adipose-derived MSC. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Elevated IL-6 secretion by MSC has been detected after interaction with malignant cells in several epithelial, hematopoietic and mesenchymal cancers.

    “Secretion of elevated levels of IL-6 by MSC has been detected upon interaction with malignant cells in several epithelial, hematopoietic and mesenchymal cancers (Table 2) [43, 69, 76, 77, 82, 115–119].”
    Quote in the paperSubstantial claim8 of 10 sources checked
    • cites [43] Xu, 2012, Bone marrow-derived mesenchymal stromal cells are attracted by multiple myeloma cell-produced chemokine CCL25 and favor myeloma cell growth in vitro and in vivo, Stem Cells source
    • cites [69] Ko, 2012, HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts, J. Clin. Invest. source

      The Figure 6 text reports increased IL6 mRNA in bone marrow- and adipose-derived MSCs after exposure to medium conditioned by ovarian cancer cells. It does not establish elevated IL-6 secretion by those MSCs, and this paper does not document that response across epithelial, hematopoietic and mesenchymal cancers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [76] Arnulf, 2007, Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma, Leukemia source
    • cites [77] Corre, 2007, Bone marrow mesenchymal stem cells are abnormal in multiple myeloma, Leukemia source

      The Results and Discussion (page numbers unavailable) report that bone marrow MSCs from multiple myeloma patients secreted more IL-6 than those from healthy donors. The Discussion also describes a myeloma-cell factor that can stimulate MSC IL-6 production. This supports the hematopoietic-cancer example, but the paper does not establish the claim across epithelial and mesenchymal cancers or show that the measured increase occurred specifically after malignant-cell interaction. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [82] Spaeth, 2009, Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression, PLoS One source

      The Results section (‘MSC secreted growth factors support Skov-3 cell proliferation’; page unavailable) reports significantly increased IL-6 secretion by MSC after exposure to conditioned medium from Skov-3 ovarian cancer cells. The Discussion also mentions IL-6 signaling in earlier breast-cancer work, but this paper does not establish elevated MSC IL-6 secretion across hematopoietic and mesenchymal cancers. It therefore supports the epithelial-cancer example, not the full range of cancers in the citing sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [115] Liu, 2011, Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks, Cancer Res. source

      The Results section on the cytokine network reports increased IL-6 gene expression in both mesenchymal and breast cancer cells after co-culture, along with increased IL-6 protein in the co-culture. It does not establish that the extra secreted protein came specifically from MSCs, or examine interactions across hematopoietic and mesenchymal cancers. The broader cancer-type claim is therefore unsupported by this paper. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [116] Walter, 2009, Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells, Oncogene source

      The Results report IL-6 secretion by adipose stromal cells and its role in breast cancer cell migration and invasion. The Discussion says the stromal cells came from cancer-free donors and had not been exposed to a tumor environment. The paper therefore does not establish that interaction with malignant cells elevated IL-6 secretion, or document that effect across epithelial, hematopoietic and mesenchymal cancers. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [117] Ara, 2009, Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells, Cancer Res. source

      The Results and Discussion (page not provided) report that bone-marrow mesenchymal stromal cells increased IL-6 production when exposed to neuroblastoma-cell products. The Discussion also describes a comparable response in myeloma, but the paper does not establish increased MSC secretion upon interaction with malignant cells across the full range of epithelial, hematopoietic and mesenchymal cancers named in the sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [118] Bian, 2010, Human mesenchymal stem cells promote growth of osteosarcoma: involvement of interleukin-6 in the interaction between human mesenchymal stem cells and Saos-2, Cancer Sci. source

      The section on paracrine interaction reports that IL-6 secretion by human MSCs increased when they were exposed to conditioned medium from Saos-2 osteosarcoma cells. This supports the claim for a mesenchymal cancer, but the paper does not establish elevated MSC IL-6 secretion after interaction with malignant cells across several epithelial and hematopoietic cancers. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [119] Lescarbeau, 2012, In vitro model of metastasis to bone marrow mediates prostate cancer castration resistant growth through paracrine and extracellular matrix factors, PLoS One source

      The Results report that LNCaP prostate cancer cells induce osteogenic differentiation of hMSCs and that osteogenically differentiated hMSCs secrete more IL-6. The authors suggest, rather than establish, that this explains increased IL-6 during interaction with the cancer cells. This paper provides a prostate cancer example, not evidence for the other cancer types named in the collective, multi-citation sentence. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    The tumor-supporting properties of MSC, such as immunomodulation, angiogenesis, cell survival and migration, often appear enhanced in MSC populations derived from tumors.

    “The tumor-supporting properties of MSC (immunomodulation, angiogenesis, cell survival or migration) often seem to be enhanced in tumor-derived MSC populations [45, 74, 75].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [45] McLean, 2011, Human ovarian carcinoma-associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production, J. Clin. Invest. source

      The Results (page unavailable) show that ovarian cancer-associated MSCs promoted more tumor growth than healthy-donor MSCs, supporting an enhanced tumor-supporting effect in this setting. But the Results found no difference in vascular density or apoptosis between tumors with cancer-associated and control MSCs; the paper does not establish that immunomodulation or migration are enhanced in tumor-derived MSCs. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [74] Yan, 2013, Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1–MMP9 axis, Hepatology source
    • cites [75] Pasquet, 2010, Hospicells (ascites-derived stromal cells) promote tumorigenicity and angiogenesis, Int. J. Cancer source

      The Results (p. 7) report increased blood vessels when ovarian tumor cells were co-injected with hospicells, and the Discussion (p. 8) notes their immunosuppressive ability. But the paper describes hospicells as MSC-like rather than definitively MSC, and does not compare tumor-derived with other MSC populations across the listed properties or establish that enhancement is common. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Most MSC-secreted factors form a common core regardless of tissue origin, including overlapping anti-apoptotic, immunomodulatory, anti-scarring, supportive, angiogenic and chemoattractant factors such as IL6, CCL2, PAI-1, TGFβ1, CD106 and VEGF.

    “The bulk of MSC-secreted factors comprises a common core, independently of their tissue of origin, including an overlapping set of anti-apoptotic, immunomodulatory, anti-scarring, supportive, angiogenic and chemoattractant factors such as interleukin-6 (IL6), chemokine C-C motif ligand 2 (CCL2), PAI-1, transforming growth factor-beta1 (TGFβ1), CD106 and vascular endothelial growth factor (VEGF) [”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [11] Meirelles Lda, 2009, Mechanisms involved in the therapeutic properties of mesenchymal stem cells, Cytokine Growth Factor Rev. source

      Table 1 (section 4, page unavailable) lists the six functional categories and includes IL-6, CCL2, TGF-β and VEGF among factors associated with cultured MSCs. It does not establish that most secreted factors form a common core independent of tissue origin, and it does not list PAI-1 or CD106 as secreted factors. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [67] Kilroy, 2007, Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors, J. Cell Physiol. source
  • Premisecitation

    Bone marrow-derived MSC and adipose-derived stem/stromal cells can also enhance cancer cell migration, invasion and metastasis through release of IL-6 in the tumor microenvironment.

    “BM-MSC and ASC could also potentiate cancer cell migration, invasion and metastasis via the release of IL-6 in the tumor microenvironment [116, 120].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [116] Walter, 2009, Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells, Oncogene source

      The Results section reports that depleting IL-6 from ASC-conditioned medium reduced breast cancer cell migration and invasion. The paper does not establish that ASC-derived IL-6 promotes metastasis; its Discussion describes IL-6-associated metastasis in bone marrow as a finding from another study. No page numbers are available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [120] Touboul, 2013, Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model, J. Transl. Med. source

      The Results (page unavailable) report that IL-6 increased ovarian cancer cell migration and invasion, and that blocking its receptor reduced infiltration in an amniotic membrane model. The study used amniotic MSCs, not bone marrow-derived MSCs or adipose-derived cells, and modeled early invasion rather than demonstrating metastasis. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Premisecitation

    Once in the tumor microenvironment, MSC can enhance tumorigenesis by differentiating into tumor-nurturing stroma such as tumor-associated fibroblasts and myofibroblasts, by direct cell contact with cancer cells, or by releasing paracrine factors.

    “There they can potentiate further tumorigenesis via differentiation into tumor-nurturing stroma (TAF, myofibroblasts) [82, 104], direct cell contact interaction with cancer cells [105, 106] or release of paracrine factors (Table 2).”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [82] Spaeth, 2009, Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression, PLoS One source
    • cites [104] Direkze, 2004, Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts, Cancer Res. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [105] Roorda, 2010, Mesenchymal stem cells contribute to tumor cell proliferation by direct cell-cell contact interactions, Cancer Invest. source
    • cites [106] Khakoo, 2006, Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma, J. Exp. Med. source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    IL-6 is an MSC-secreted inflammatory cytokine with pro-survival, pro-growth and pro-angiogenic activities, and it has been implicated in tumor progression in various cancers including breast cancer.

    “IL-6 is an MSC-secreted inflammatory cytokine displaying pro-survival, pro-growth and pro-angiogenic activities [11], which has been implicated in tumor progression of various cancers including breast cancer [113, 114].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [11] Meirelles Lda, 2009, Mechanisms involved in the therapeutic properties of mesenchymal stem cells, Cytokine Growth Factor Rev. source

      Section 3.2.4 says cultured MSCs secrete IL-6 as part of their support for hematopoiesis, and Section 3.2.5 and Table 1 classify it among angiogenic factors. Section 3.2.5 describes anti-apoptotic effects of MSC-conditioned medium containing IL-6, but does not establish IL-6 itself as the cause or clearly establish its individual pro-growth activity. The tumor-progression clause is cited to [113, 114], not to this source, and is not part of this verdict. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [113] Sasser, 2007, Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer, FASEB J. source
    • cites [114] Sansone, 2007, IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland, J. Clin. Invest. source

  • May combine two claims.

    Premisecitation

    MSC can be mobilized and recruited to active tumor sites, where they can become part of the tumor microenvironment.

    “MSC can be mobilized and recruited to active tumor sites, where they can incorporate into the tumor’s microenvironment [5, 68, 100–103].”
    Quote in the paperSubstantial claim3 of 6 sources checked
    • cites [5] Spaeth, 2008, Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells, Gene Ther. source
    • cites [68] Kidd, 2012, Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma, PLoS One source
    • cites [100] Karnoub, 2007, Mesenchymal stem cells within tumour stroma promote breast cancer metastasis, Nature source
    • cites [101] Ishii, 2003, Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction, Biochem. Biophys. Res. Commun. source
    • cites [102] Mishra, 2008, Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells, Cancer Res. source
    • cites [103] Hung, 2005, Mesenchymal stem cell targeting of microscopic tumors and tumor stroma development monitored by noninvasive in vivo positron emission tomography imaging, Clin. Cancer Res. source

      The Discussion (p. 7) reports that intravenously administered human MSCs engrafted in microscopic tumors and contributed to tumor stroma, supporting recruitment and incorporation. It also says that whether tumors mobilize endogenous MSCs from bone marrow remains undetermined, so the mobilization part is not established by this study. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Small resting CD90+ breast cancer cells form tumors with high efficiency, requiring fewer than 100 cells per injection, and do so independently of supportive stroma or adipose-derived stem/stromal cells.

    “Small (low light scatter) resting CD90+ breast cancer cells give rise to tumors with high efficiency (<100 cells/injection) [90, 99], independently of supportive stroma/ASC [51].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [90] Donnenberg, 2010, Localization of CD44 and CD90 positive cells to the invasive front of breast tumors, Cytometry B Clin. Cytom. source

      The Discussion (‘Size Matters’; page unavailable) reports tumor formation from ≤60 CD44+/CD90+ low-light-scatter cells in a previous study. This paper’s own experiments used 100 sorted cells per site and found tumors at 5%–25% of sites. Neither experiment establishes independence from supportive cells: the Discussion says all injected populations received irradiated tumor cells and Matrigel, potentially providing a niche effect. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [99] Donnenberg, 2006, Tumorigenic epithelial stem cells and their normal counterparts, Ernst Schering Found Symp. Proc. source
    • cites [51] Zimmerlin, 2011, Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates, Tissue Eng. Part A source

  • May combine two claims.

    Premiseown data

    The authors' in vivo mouse model showed tumor growth kinetics and incidence similar to dormant cancer cell line models, unlike studies using aggressive cancer cell lines that often produce tumors larger than 100 mm3 within a month after implantation.

    “Importantly, our in vivo mouse model displayed tumor growth kinetics and incidence similar to dormant cancer cell line models [93–96], in contrast to studies relying on aggressive cancer cell lines and resulting often into >100mm3 tumors less than a month after implantation [7].”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [93] Naumov, 2006, A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype, J. Natl. Cancer Inst. source
    • cites [94] Goodison, 2003, Prolonged dormancy and site-specific growth potential of cancer cells spontaneously disseminated from nonmetastatic breast tumors as revealed by labeling with green fluorescent protein, Clin. Cancer Res.
    • cites [95] Suzuki, 2006, Dormant cancer cells retrieved from metastasis-free organs regain tumorigenic and metastatic potency, Am. J. Pathol. source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [96] Almog, 2009, Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype, Cancer Res. source
    • cites [7] Donnenberg, 2010, Regenerative therapy after cancer: what are the risks?, Tissue Eng. Part B Rev. source

  • May combine two claims.

    Premisecitation

    All MSC populations share basic immunophenotypic and functional similarities, but high-resolution techniques reveal differences that are also reflected in variability of their secretome.

    “Although all MSC populations share basic similarities immunophenotypically and functionally, differences can be demonstrated using high resolution techniques [52, 53] and are reflected in variability within their secretome [7, 54].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [52] Jansen, 2010, Functional differences between mesenchymal stem cell populations are reflected by their transcriptome, Stem Cells Dev. source
    • cites [53] Noël, 2008, Cell specific differences between human adipose-derived and mesenchymal-stromal cells despite similar differentiation potentials, Exp. Cell Res. source

      The phenotypic characterization (p. 5) reports shared surface markers in adipose-derived and bone marrow-derived stromal cells. The proteomic and genomic characterization (p. 6) finds broadly similar profiles but differences that distinguish those two populations. The paper does not establish the sentence’s broader claim about all MSC populations; the secretome clause is attached to different citations. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [7] Donnenberg, 2010, Regenerative therapy after cancer: what are the risks?, Tissue Eng. Part B Rev. source
    • cites [54] Klopp, 2012, Omental adipose tissue-derived stromal cells promote vascularization and growth of endometrial tumors, Clin. Cancer Res. source

  • May combine two claims.

    Premisecitation

    Mesenchymal stem/stromal cells possess pro-regenerative properties: they can differentiate into multiple lineages, home to injury and inflammation, and exert paracrine immunomodulatory, pro-angiogenic, anti-apoptotic and pro-proliferative effects.

    “Mesenchymal stem/stromal cells (MSC) exhibit a set of pro-regenerative features (multi-lineage differentiation capacity, homing to sites of injury and inflammation, and paracrine immunomodulatory, pro-angiogenic, anti-apoptotic and pro-proliferative effects, Figure 1) that make them an attractive candidate for modulation of immune disorders and regenerative therapy approaches [1–3].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [1] Gimble, 2007, Adipose-derived stem cells for regenerative medicine, Circ. Res. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [2] Caplan, 2007, Adult mesenchymal stem cells for tissue engineering versus regenerative medicine, J. Cell. Physiol. source
    • cites [3] Casteilla, 2011, Adipose-derived stromal cells: their identity and uses in clinical trials, an update, World J. Stem Cells source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Bone marrow-derived MSC and adipose-derived stem/stromal cells can secrete a combination of anti-apoptotic and angiogenic factors, including HGF, SDF-1/CXCL12, CD106 and VEGF, which can promote tumor growth, local angiogenesis and metastasis.

    “BM-MSC and ASC can also secrete a combination of anti-apoptotic and angiogenic factors [121], including HGF, SDF-1/CXCL12, CD106 (sVCAM) and VEGF which can promote tumor growth, local angiogenesis and metastasis [42, 84, 122–127].”
    Quote in the paperSubstantial claim4 of 9 sources checked
    • cites [121] Rehman, 2004, Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells, Circulation source
    • cites [42] Martin, 2003, Growth and angiogenesis of human breast cancer in a nude mouse tumour model is reduced by NK4, a HGF/SF antagonist, Carcinogenesis source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [84] Beckermann, 2008, VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma, Br. J. Cancer source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [122] Sun, 2005, Correlation between melanoma angiogenesis and the mesenchymal stem cells and endothelial progenitor cells derived from bone marrow, Stem Cells Dev. source
    • cites [123] Zhang, 2010, Bone marrow mesenchymal stem cells induce angiogenesis and promote bladder cancer growth in a rabbit model, Urol. Int. source
    • cites [124] Orimo, 2005, Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion, Cell source
    • cites [125] Jedeszko, 2009, Fibroblast hepatocyte growth factor promotes invasion of human mammary ductal carcinoma in situ, Cancer Res. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [126] Edakuni, 2001, Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma, Pathol. Int. source
    • cites [127] Boomsma, 2012, Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis, PLoS One source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    This could lead to promotion of a pro-resting cancer stem cell niche for the most therapy-resistant stem-like cells, or to recruitment and promotion of tumorigenesis for more active progenitor cells.

    “This may result into promotion of a pro-resting CSC niche [152, 153] for the most therapy-resistant stem-like cells, or recruitment and promotion of tumorigenesis for more active progenitor cells.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [152] Borovski, 2011, Cancer stem cell niche: the place to be, Cancer Res. source

      The Introduction says the CSC niche shelters cancer stem cells from genotoxic insults and contributes to their therapy resistance. It does not describe the niche as promoting a resting or quiescent state. The citation is attached to the niche claim, so the subsequent alternative about active progenitor cells is not the basis of this verdict. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [153] Garofalo, 2006, Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli, Clin. Cancer Res. source

      The Discussion reports that leptin and its receptor negatively correlated with Ki-67 in metastases, but it does not connect that observation to a resting cancer stem-cell niche. Searches for quiescent, therapy-resistant stem-like cells and progenitor-cell recruitment found no passage addressing the cited claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    CCL5, also called RANTES, is another MSC-secreted pro-metastasis cytokine that can be secreted upon interaction with cancer cells and is associated with tumor progression and invasion in various cancers.

    “Another MSC-secreted pro-metastasis cytokine, CCL5 (RANTES), can be secreted upon interaction with cancer cells and is associated with tumor progression and invasion in various cancers [73, 87, 100, 142–144].”
    Quote in the paperNot a substantial claim2 of 6 sources checked
    • cites [73] Muehlberg, 2009, Tissue-resident stem cells promote breast cancer growth and metastasis, Carcinogenesis source

      The tumor-growth section reports that adipose-derived stem cells produced RANTES when exposed to breast cancer cells, and the Discussion reports that RANTES enhances breast cancer cell invasion and metastasis. The passages do not establish an association between RANTES and tumor progression and invasion across various cancers; they address breast cancer. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [87] Xu, 2009, Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis, Cancer Lett. source
    • cites [100] Karnoub, 2007, Mesenchymal stem cells within tumour stroma promote breast cancer metastasis, Nature source
    • cites [142] Schaffler, 2006, Secretion of RANTES (CCL5) and interleukin-10 from mesenteric adipose tissue and from creeping fat in Crohn's disease: regulation by steroid treatment, J. Gastroenterol. Hepatol. source
    • cites [143] Pinilla, 2009, Tissue resident stem cells produce CCL5 under the influence of cancer cells and thereby promote breast cancer cell invasion, Cancer Lett. source
    • cites [144] Zhang, 2009, Role of CCL5 in invasion, proliferation and proportion of CD44+/CD24− phenotype of MCF-7 cells and correlation of CCL5 and CCR5 expression with breast cancer progression, Oncol. Rep. source

      The Discussion reports that CCL5 is a promalignant factor in several cancers, and the Introduction reports increased invasion of MCF-7 breast cancer cells after CCL5 treatment. Our copy does not establish that mesenchymal stem cells secrete CCL5 upon interaction with cancer cells; it studies CCL5’s effects and its expression in breast cancer tissue. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    CCL5 can be secreted by both bone marrow-derived MSC and adipose-derived stem/stromal cells, and it has pro-proliferative effects on breast cancer cell lines.

    “CCL5 can be secreted by both BM-MSC and ASC [100, 144] and displays pro-proliferative activities on breast cancer cell lines [145, 146].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [100] Karnoub, 2007, Mesenchymal stem cells within tumour stroma promote breast cancer metastasis, Nature source
    • cites [144] Zhang, 2009, Role of CCL5 in invasion, proliferation and proportion of CD44+/CD24− phenotype of MCF-7 cells and correlation of CCL5 and CCR5 expression with breast cancer progression, Oncol. Rep. source
    • cites [145] Murooka, 2009, CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation, Biochem. Biophys. Res. Commun. source
    • cites [146] Park, 2012, Growth factor-activated stem cell circuits and stromal signals cooperatively accelerate non-integrated iPSC reprogramming of human myeloid progenitors, PLoS One source

      The Results section reports chemokines in cord-blood/BMSC co-culture supernatants, but names CCL2 rather than CCL5. Searches for CCL5 and adipose-derived stem cells found no passage establishing that either cell type secretes CCL5. The breast-cancer proliferation clause has separate citations in the citing sentence and is not attributed to this paper. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In the authors' own experiments with breast cancer clinical isolates, dormant-like tumor-initiating cells did not respond to MSC signals, whereas actively dividing cancer cells benefited from supportive MSC.

    “Our own data using breast cancer clinical isolates have suggested that dormant-like tumor-initiating cells do not respond to MSC signals, unlike actively dividing cancer cells which benefited from the presence of supportive MSC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Even though VEGF levels secreted by adipose-derived stem/stromal cells were moderate, the authors could still detect development of human blood vessels within tumor xenografts coinjected with human adipose-derived stem/stromal cells.

    “Although levels of VEGF secreted by ASC were moderate, we could still detect the development of human blood vessels within tumor xenografts coinjected with human ASC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Resting tumor cells did not respond to local adipose-derived stem/stromal cell signals, although they were consistently able to generate tumors from a limited number of injected cells.

    “Yet, resting cells were not responsive to local ASC signals, although they were consistently able to generate tumors from a limited number of injected cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Studies of MSC-cancer cell interactions are sometimes contradictory: within the same cancer model, and occasionally with identical cancer cell lines, MSC can either promote or inhibit tumor progression.

    “These studies are sometimes contradictory, and MSC can be shown to either promote or inhibit tumor progression within the same cancer model (Table 1), occasionally using identical cancer cell lines.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In various animal models, pre- or co-injected cancer cell lines recruit MSC in vivo, and this recruitment is followed by either promotion or inhibition of tumor growth or metastasis.

    “A number of studies have stressed the in vivo recruitment of MSC by pre- or co-injected cancer cell lines in a variety of animal models and the subsequent promotion (or inhibition) of either tumor growth or metastasis (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mesenchymal stem/stromal cells respond to tumor-associated inflammatory signals and migrate to malignant sites.

    “Unfortunately, the tumor and wound microenvironments share a lot of similarities [4] and MSC have been shown to similarly respond to tumor-associated inflammatory signals and home to malignant sites [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Spaeth, 2008, Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells, Gene Ther. source

  • May combine two claims.

    Interpretationreasoning

    Models that use aggressive cancer cell lines are of little relevance to regenerative therapy after cancer, but they may be better suited for assessing possible suppressive effects of MSC on rapidly growing, high-grade, therapy-unresponsive tumors.

    “Models using aggressive cell lines have little relevance to regenerative therapy after cancer, but may be more appropriate for evaluating potential suppressive effects of MSC on rapidly growing high-grade therapy unresponsive tumors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Late recurrence is well documented and directly evidences the persistence of tumor-initiating cells at a subclinical level, a state called cancer dormancy.

    “Late recurrence is well documented and provides direct evidence for the persistence of tumor-initiating cells at a subclinical level, referred as cancer dormancy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Although the secretome of MSC from different tissues can differ somewhat, it contains a shared set of cytokines, including CCL2, CCL5, IL-6, TGFβ and VEGF, that have been linked to tumor growth and/or metastasis.

    “The secretome of MSC isolated from various tissues may partially diverge, but it includes a core of cytokines (i.e. CCL2, CCL5, IL-6, TGFβ, VEGF), which have been implicated in tumor growth and/or metastasis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Many current tissue repair strategies make use of the paracrine or restorative properties of mesenchymal stem/stromal cells.

    “Many current tissue repair approaches exploit paracrine (immunomodulatory, pro-angiogenic, anti-apoptotic and pro-survival effects) or restoring (functional or structural tissue repair) properties of mesenchymal stem/stromal cells (MSC).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Studies of tumor-MSC interactions have shown MSC tumor-supporting paracrine activities, including local immunosuppression and angiogenesis, promotion of tumor growth and invasion such as acquisition of EMT or CSC phenotype and ECM remodeling, and inhibition of tumor apoptosis or necrosis, across a wide range of cancers.

    “Tumor-MSC interactions studies have revealed MSC tumor-supporting paracrine activities (local immunosuppression and angiogenesis, promotion of tumor growth and invasion (i.e. acquisition of epithelial-mesenchymal transition (EMT)/CSC phenotype or ECM remodeling), inhibition of tumor apoptosis or necrosis) in a large spectrum of cancers (Table 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Tumor relapse implies that rare tumor-initiating cancer cells survive anti-cancer therapy, remain dormant in particular niches, and can later be reactivated by unknown triggers.

    “Tumor relapse implies the persistence of rare subsets of tumor-initiating cancer cells which can escape anti-cancer therapies and lie dormant in specific niches awaiting reactivation via unknown stimuli.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In these studies, IL-6 released by MSC supported tumor growth by stimulating cancer cell proliferation and survival or by protecting cancer cells from apoptosis.

    “In these studies, MSC-released IL-6 supported tumor growth by stimulating cancer cell proliferation and survival or protecting from apoptosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Although bidirectional cross-talk between MSC and aggressive cancer cells is well documented, the specific interactions between MSC and dormant-like tumor-initiating cells are still poorly established.

    “While bi-directional cross-talk between MSC and aggressive cancer cells is well documented, specific interactions between MSC and dormant-like tumor-initiating cells remain poorly established.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    MSC release elevated levels of TGFβ after interacting with breast and prostate cancer cells, which stimulates the proliferative and migratory capacities of those cancer cells.

    “MSC have also been shown to release elevated levels of TGFβ upon interaction with breast and prostate cancer [32, 35, 81], resulting into stimulation of the proliferative and migratory capacities of the cancer cells.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [32] Hung, 2012, Hypoxia-induced secretion of TGF-beta 1 in mesenchymal stem cell promotes breast cancer cell progression, Cell Transplant. source
    • cites [35] Ye, 2012, Human bone marrow-derived mesenchymal stem cells produced TGFbeta contributes to progression and metastasis of prostate cancer, Cancer Invest. source
    • cites [81] Razmkhah, 2011, Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL-4, IL-10 and TGF-beta1 and upregulate expression of regulatory molecules on T cells: do they protect breast cancer cells from the immune response?, Cell Immunol. source

  • May combine two claims.

    Premisecitation

    Early cancer recurrence after treatment for hematopoietic or epithelial cancer is often marked by very aggressive active disease, which is a clear contraindication to regenerative reconstructive therapy.

    “Early cancer recurrence following hematopoietic or epithelial cancer treatment is often characterized by very aggressive active disease [7], a clear contraindication to regenerative reconstructive therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Donnenberg, 2010, Regenerative therapy after cancer: what are the risks?, Tissue Eng. Part B Rev. source

  • May combine two claims.

    Premisenone given

    Patients with responsive disease who enter clinical remission remain at risk for late relapse, which implies the persistence of a distinct population of dormant cancer-initiating cells.

    “On the other hand, patients with responsive disease who enter clinical remission are nonetheless at risk for late relapse, implying the persistence of a distinct population of dormant cancer-initiating cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Findings from multiple laboratories suggest that MSC have multiple effects on tumor cells, which may depend on the state of the tumor cell, the properties of specific MSC populations, and interactions with other cell types such as tumor-infiltrating immune cells.

    “The results from multiple laboratories suggest that the effects of MSC on tumor cells are multiple and may depend on the state of the tumor cell, the properties of specific MSC populations, and interactions with other cell types, such as tumor infiltrating immune cells..”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MCP1 is a critical chemoattractant that recruits macrophages into tumors and supports angiogenesis in breast cancer, and it may contribute to indirect communication between MSC and cancer cells by recruiting tumor-resident macrophages.

    “MCP1 is a critical chemoattractant responsible for the recruitment of macrophages into tumor and for angiogenesis in breast cancer [131, 132], and may contribute to indirect crosstalk between MSC and cancer cells via recruitment of tumor-resident macrophages.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [131] Ueno, 2000, Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer, Clin. Cancer Res.
    • cites [132] Moore, 1999, Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis, Nat. Med. source
30 of 30

  • The paper relies on this without support.

    Cancer treatment frequently uses non-selective tumor-ablative methods that can produce major functional loss or disfigurement.

    “Cancer treatment often relies on non-selective tumor ablative techniques that can result into severe functional impairments or disfiguring damages.”
1 of 1

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?

  • Several factors can influence the interaction between mesenchymal stromal cells and cancer cells: the origin and pre-treatment of mesenchymal stromal cells, the cancer type, and various in vitro and in vivo system-related factors.

    “Several factors can influence the interaction between MSCs and cancer cells: the origin and pre-treatment of MSCs, the cancer type and various in vitro and in vivo system-related factors (the ratio of MSCs and cancer cells, simultaneous or sequential injection of MSCs and cancer cells, local versus systemic MSC delivery or kinetics of carcinogenesis) [22].”

    From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [22]

Cites

Flagged first, then by citations

9 of the 183 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Czerny, 1895, Plastischer Ersatz der Brustdruse durch ein Lipom, Chir Kong Verhandl, 2, 216

Cited by

Sorted by citations

Related

Authors
Zimmerlin, L., Park, T. S., Zambidis, E. T., Donnenberg, V. S., & Donnenberg, A. D.
Affiliations
  • Johns Hopkins University (US)
  • University of Pittsburgh (US)
Corresponding author
  • Zimmerlin, Ludovic
  • Donnenberg, Albert D.
ORCID
Venue
Biochimie
Publisher
Elsevier BV
Published
2013-12
Volume
95
Issue
12
Pages
2235-2245
ISSN
  • 0037-9042 (ISSN-L)
  • 0300-9084
DOI
10.1016/j.biochi.2013.05.010
PMC
PMC3825748
OpenAlex
W1991701652
Cited by
168
References
183
Citations by year
2026: 4 · 2025: 5 · 2024: 8 · 2023: 13 · 2022: 9 · 2021: 19 · 2020: 10 · 2019: 20 · 2018: 15 · 2017: 14 · 2016: 26 · 2015: 13 · 2014: 11 · 2013: 1
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochimie (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Department of Defense (BC032981, BC044784)
  • NIH (R01CA 114246)
  • National Heart, Lung, and Blood Institute (R01-HL-085819)
  • Hillman Foundation
  • Glimmer of Hope Foundation
  • Commonwealth of Pennsylvania
  • NHLBI
  • Department of Defense Biomedical Translational Initiative
  • Maryland Stem Cell Research Fund
  • Maryland Stem Cell Research Fund (MSCFR) Postdoctoral Fellowship (2009-MSCRF III-106570)
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Urology › Periodontal Regeneration and Treatments
Keywords
mesenchymal stem cells, secretome, regenerative therapy, tumor remission, tumor recurrence, cancer stem cells, paracrine signaling, tumor microenvironment, breast cancer, cytokines, angiogenesis, immunomodulation
MeSH terms
Humans, Neoplasm Metastasis, Neoplasm Recurrence, Local, Neoplasms, Neoplastic Stem Cells, Proteome, Regenerative Medicine, Cell Proliferation, Mesenchymal Stem Cells

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.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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