Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation

Dinesh K. Ahirwar, Mohd W. Nasser, Madhu M. Ouseph, Mohamad Elbaz, Maria C. Cuitiño, Raleigh D. Kladney, Sanjay Varikuti, Kirti Kaul, Abhay R. Satoskar, Bhuvaneswari Ramaswamy, Xiaoli Zhang, Michael C. Ostrowski, Gustavo Leone, Ramesh K. Ganju

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12 in mice and used a fibroblast-specific Cre transgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)4428-4442
Number of pages15
JournalOncogene
Volume37
Issue number32
DOIs
StatePublished - Aug 9 2018

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Fibroblasts
Breast Neoplasms
Neoplasm Metastasis
Blood Vessels
Endothelial Cells
Neoplasms
Survival
Chemokine CXCL12
Tumor Microenvironment
Tight Junctions
Capillary Permeability
Transgenes
Permeability
Proteins
Biomarkers
Alleles
Recurrence
Growth
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Ahirwar, D. K., Nasser, M. W., Ouseph, M. M., Elbaz, M., Cuitiño, M. C., Kladney, R. D., ... Ganju, R. K. (2018). Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation. Oncogene, 37(32), 4428-4442. https://doi.org/10.1038/s41388-018-0263-7

Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation. / Ahirwar, Dinesh K.; Nasser, Mohd W.; Ouseph, Madhu M.; Elbaz, Mohamad; Cuitiño, Maria C.; Kladney, Raleigh D.; Varikuti, Sanjay; Kaul, Kirti; Satoskar, Abhay R.; Ramaswamy, Bhuvaneswari; Zhang, Xiaoli; Ostrowski, Michael C.; Leone, Gustavo; Ganju, Ramesh K.

In: Oncogene, Vol. 37, No. 32, 09.08.2018, p. 4428-4442.

Research output: Contribution to journalArticle

Ahirwar, DK, Nasser, MW, Ouseph, MM, Elbaz, M, Cuitiño, MC, Kladney, RD, Varikuti, S, Kaul, K, Satoskar, AR, Ramaswamy, B, Zhang, X, Ostrowski, MC, Leone, G & Ganju, RK 2018, 'Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation', Oncogene, vol. 37, no. 32, pp. 4428-4442. https://doi.org/10.1038/s41388-018-0263-7
Ahirwar, Dinesh K. ; Nasser, Mohd W. ; Ouseph, Madhu M. ; Elbaz, Mohamad ; Cuitiño, Maria C. ; Kladney, Raleigh D. ; Varikuti, Sanjay ; Kaul, Kirti ; Satoskar, Abhay R. ; Ramaswamy, Bhuvaneswari ; Zhang, Xiaoli ; Ostrowski, Michael C. ; Leone, Gustavo ; Ganju, Ramesh K. / Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation. In: Oncogene. 2018 ; Vol. 37, No. 32. pp. 4428-4442.
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