Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment
Open accessAbstract
Significance: The recruitment of host stromal cells, such as macrophages and mesenchymal stem cells (MSCs), to the primary tumor is a critical step toward cancer malignancy. We have identified signals that are exchanged between breast cancer cells (BCCs) and MSCs. This signaling increases the recruitment of both MSCs and macrophages to primary tumors and increases metastasis of BCCs to lymph nodes and lungs. Reduced oxygen levels (hypoxia) in breast cancers are associated with increased risk of metastasis and decreased patient survival. We show that hypoxia stimulates signaling between BCCs and MSCs due to the activity of hypoxia-inducible factors (HIFs). Drugs that block HIF activity prevent signaling and macrophage recruitment, which suggests that they may be useful additions to breast cancer therapy.
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HIF-1α or HIF-2α expression in TAMs is associated with tumor progression and/or poor prognosis in multiple tumor types.
“Both HIF-1α or HIF-2α expression in TAMs have been associated with tumor progression and/or poor prognosis in multiple tumor types, whereas lack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6 [73–76].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [75]
The section ‘HIF-Dependent BCC-MSC Interactions Promote TAM and Myeloid-’ reports that hypoxia induces HIF-1α and HIF-2α in macrophages, activating genes with prometastatic functions. The introduction also links TAM density—not HIF expression in TAMs—to metastasis and mortality in breast cancer. The paper does not establish the claimed association between HIF expression in TAMs and poor prognosis across multiple tumor types; its HIF-knockdown experiments target breast cancer cells, not TAMs. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6.
“Both HIF-1α or HIF-2α expression in TAMs have been associated with tumor progression and/or poor prognosis in multiple tumor types, whereas lack of HIF-1α or HIF-2α in TAMs decreases metastasis, cell proliferation, and expression of pro-inflammatory cytokines such as IL-6 [73–76].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [75]
In the section on the syngeneic mouse mammary carcinoma model (page not available), HIF knockdown in breast cancer cells reduced metastasis; HIF-1α knockdown also reduced primary tumor growth. The knockdown was not in TAMs, and the cited passages do not establish reduced cell proliferation or IL-6 expression. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHypoxia is a hallmark of most solid tumors and a common trait of the tumor microenvironment associated with cancer progression and metastasis.
“Hypoxia is a hallmark of most solid tumors and a common trait of TME that is associated with cancer progression and metastasis8–10.”
Hypoxia plays a crucial role in tumor growth, metastasis, and drug resistance in solid tumors.
“Hypoxia plays a crucial role in tumor growth, metastasis, and drug resistance in solid tumors8,9”
Hypoxic signaling in MDSCs and macrophages directly contributes to tumor progression by promoting an immunosuppressive phenotype and stimulating angiogenesis.
“Hypoxic signaling in MDSCs and macrophages directly contributes to tumor progression by promoting an immunosuppressive phenotype and stimulating angiogenesis”
From Hypoxic control of metastasis (2016) · cites this paper as [63]
MSCs express CXCL10, which binds CXCR3 on breast cancer cells, and breast cancer cells produce CXCL16, which binds CXCR6 on MSCs and promotes their recruitment to the primary tumor.
“MSCs express the chemokine CXCL10, which binds to its cognate receptor CXCR3 on BCCs, and BCCs produce the chemokine CXCL16, which binds to its cognate receptor CXCR6 on MSCs and promotes their recruitment to the primary tumor [41].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
HIF-1α/HIF-2α double knockdown in 4T1 mouse mammary carcinoma cells inhibited recruitment of TAMs and MDSCs to primary tumors and metastasis of breast cancer cells to lymph nodes and lungs after mammary fat pad injection.
“HIF-1α/HIF-2α double knockdown in 4T1 cells inhibited the recruitment of TAMs and MDSCs to primary tumors and the metastasis of BCCs to lymph nodes and lungs after mammary fat pad injection [41].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
CXCL10MSC→CXCR3BCC signaling stimulates CXCL16BCC→CXCR6MSC signaling and vice versa.
“In addition, CXCL10MSC → CXCR3BCC signaling stimulates CXCL16BCC → CXCR6MSC signaling and vice versa [41], providing a molecular basis for the stimulatory effect of co-culture.”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
Expression of PGF, CXCR3, and CXCL16 by breast cancer cells is induced by hypoxia in a HIF-dependent manner.
“Expression of PGF, CXCR3, and CXCL16 by BCCs is induced by hypoxia in a HIF-dependent manner [40, 41].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
The hypoxia-induced signaling pathways delineated in breast cancer cell lines and mice are clinically relevant.
“suggesting that the hypoxia-induced signaling pathways delineated in BCC lines and mice are clinically relevant.”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
Hypoxia induces HIF-dependent expression by breast cancer cells of CCR5 and CSF-1, due to direct binding of HIF-1 to two sites in the 5'-flanking region of the CSF1 gene and sites in the 5'-flanking region and exon 3 of the CCR5 gene.
“Hypoxia induces the HIF-dependent expression by BCCs of CCR5 and CSF-1, due to the direct binding of HIF-1 to two sites in the 5’-flanking region of the CSF1 gene and sites in the 5’-flanking region and exon 3 of the CCR5 gene [41].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
The stimulatory effect of MSC co-culture on breast cancer metastasis was lost when HIF-1α/HIF-2α, CXCR3, or CXCL16 expression was knocked down by shRNA in breast cancer cells.
“The stimulatory effect of MSC co-culture on breast cancer metastasis was lost when HIF-1α/HIF-2α, CXCR3, or CXCL16 expression was knocked down by shRNA in BCCs [40, 41].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
Co-culture of breast cancer cells with MSCs prior to mammary fat pad injection increased recruitment of CSF1R+ F4/80+ TAMs and CD11b+ Ly6C+ MDSCs to the primary tumor in a HIF-dependent manner.
“The co-culture of BCCs with MSCs prior to mammary fat pad injection increased the recruitment of CSF1R+ F4/80+ TAMs and CD11b+ Ly6C+ MDSCs to the primary tumor in a HIF-dependent manner [41].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
Knockdown of HIF-1α/HIF-2α, CCR5, or CSF-1 expression in breast cancer cells significantly impaired recruitment of TAMs and MDSCs to the primary tumor and metastasis to lymph nodes and lungs, without affecting primary tumor growth.
“Knockdown of HIF-1α/HIF-2α, CCR5, or CSF-1 expression in BCCs significantly impaired recruitment of TAMs and MDSCs to the primary tumor, and BCC metastasis to lymph nodes and lungs, without affecting primary tumor growth [41].”
From The hypoxic tumor microenvironment: A driving force for breast cancer progression (2016) · cites this paper as [41]
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- Authors
- Chaturvedi, P., Gilkes, D. M., Takano, N., & Semenza, G. L.
- Affiliations
- Vascular Program, Institute for Cell Engineering,
- Johns Hopkins University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-05-05
- Volume
- 111
- Issue
- 20
- Pages
- E2120-9
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4034192
- OpenAlex
- W1970490725
- Cited by
- 226
- References
- 56
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 27 · 2023: 16 · 2022: 23 · 2021: 23 · 2020: 23 · 2019: 14 · 2018: 21 · 2017: 14 · 2016: 13 · 2015: 19 · 2014: 7
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- Susan G. Komen for the Cure
- Johns Hopkins University
- National Institutes of Health
- Japan Science and Technology Agency
- National Cancer Institute (K99CA181352)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079637)
- National Center for Research Resources (P40RR017447)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- triple-negative breast cancer, mesenchymal stem cells, tumor-associated macrophages, hypoxia-inducible factor, intratumoral hypoxia, macrophage recruitment, CSF-1, CXCL16, CXCR6, CXCL10, CXCR3, RANTES, CCR5, myeloid-derived suppressor cells, chemokine signaling, MDA-MB-231 cells
- MeSH terms
- Chemokine CXCL16, Animals, Hypoxia, Bone Marrow Cells, Cell Movement, Female, Humans, Lung Neoplasms, Lymphatic Metastasis, Macrophages, Male, Mammary Neoplasms, Experimental, Mice, Inbred BALB C, Neoplasm Transplantation, Signal Transduction, Gene Expression Regulation, Neoplastic, Mice, SCID, Receptors, CCR5, Chemokines, CXC, Gene Expression Profiling, Cell Line, Tumor, Receptors, Scavenger, Mice, Hypoxia-Inducible Factor 1, Chemokine CXCL10, Mesenchymal Stem Cells, Triple Negative Breast Neoplasms
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.
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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