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.

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Additional information

These authors contributed equally: Gustavo Leone, Ramesh K. Ganju.

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Acknowledgements

We are thankful to Reham S. Shehab, Sanjit Roy, Chan Fu, Mohamed Adel, and Nitika Agarwal for technical assistance. This work is supported in part by Pelotonia Idea award, Department of Defense level II breakthrough awards, and NIH R01 grants (CA109527 and CA153490) to RKG. DKA was recipient of Pelotonia Postdoctoral award.

Author contributions:

DKA, WMN, MMO, GL and RKG designed the experiments. All authors performed the experiments and collected and analyzed the data. RKG and GL supervised the studies. DKA, GL, MCO and RKG wrote the manuscript with inputs from all the authors.

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    Affiliations

    1. Department of Pathology, Ohio State University, Columbus, OH, 43210, USA

      • Dinesh K. Ahirwar
      • , Mohd W. Nasser
      • , Mohamad Elbaz
      • , Sanjay Varikuti
      • , Kirti Kaul
      • , Abhay R. Satoskar
      •  & Ramesh K. Ganju
    2. Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH, 43210, USA

      • Madhu M. Ouseph
      • , Maria C. Cuitiño
      • , Raleigh D. Kladney
      • , Michael C. Ostrowski
      •  & Gustavo Leone
    3. Comprehensive Cancer Center, Ohio State University, Columbus, OH, 43210, USA

      • Raleigh D. Kladney
      • , Bhuvaneswari Ramaswamy
      • , Michael C. Ostrowski
      • , Gustavo Leone
      •  & Ramesh K. Ganju
    4. Department of Internal Medicine, Ohio State University, Columbus, OH, 43210, USA

      • Bhuvaneswari Ramaswamy
    5. Center for Biostatistics, Ohio State University, Columbus, OH, 43210, USA

      • Xiaoli Zhang

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    Correspondence to Gustavo Leone or Ramesh K. Ganju.

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    https://doi.org/10.1038/s41388-018-0263-7