Cancer has been conceptualized as a chronic wound with a predominance of tumor promoting inflammation. Given the accumulating evidence that the microenvironment supports tumor growth, we investigated hyaluronan (HA)-CD44 interactions within breast cancer cells, to determine whether this axis directly impacts the formation of an inflammatory microenvironment. Our results demonstrate that breast cancer cells synthesize and fragment HA and express CD44 on the cell surface. Using RNA sequencing approaches, we found that loss of CD44 in breast cancer cells altered the expression of cytokine-related genes. Specifically, we found that production of the chemokine CCL2 by breast cancer cells was significantly decreased after depletion of either CD44 or HA. In vivo, we found that CD44 deletion in breast cancer cells resulted in a delay in tumor formation and localized progression. This finding was accompanied by a decrease in infiltrating CD206+ macrophages, which are typically associated with tumor promoting functions. Importantly, our laboratory results were supported by human breast cancer patient data, where increased HAS2 expression was significantly associated with a tumor promoting inflammatory gene signature. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers.
Bibliographical noteFunding Information:
Acknowledgments: The authors would like to thank Douglas Yee (funded by Masonic Cancer Center (MCC) Support grant, P30‐CA077598), and other members of the University of Minnesota Breast Cancer Translational Working Group (BrCa‐TWG), for assistance with the cell line and patient Nanostring gene expression experiments. The authors would also like to thank the Elsa Pardee foundation (L.Furcht, Allen‐Pardee Professor).
Funding: This research was funded by HHS | National Institutes of Health (NIH): Patrice M. Witschen, T32 fellowship, OD010993; American Cancer Society Clinical Scientist Development Scholar program: Andrew C. Nelson, 132574‐CSDG‐18‐139‐01‐CSM; Eastern Star Scholar program of the Minnesota Masonic Charities: Andrew C Nelson; HHS | National Institutes of Health (NIH): Kathryn L. Schwertfeger, R01HD095858; HHS | National Institutes of Health (NIH): Kathryn L. Schwertfeger, R01CA235385; Chairmanʹs Fund Professor in Cancer Research to James B. McCarthy; Nanostring experiments were supported by a developmental grant to the BrCa‐TWG.
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- Breast cancer
- Tumor microenvironment