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Open AccessArticle

Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer

1
Comparative and Molecular Biosciences Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA
2
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
3
Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA
4
University of Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA
5
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
6
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
*
Authors to whom correspondence should be addressed.
Present address: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
Cancers 2020, 12(5), 1325; https://doi.org/10.3390/cancers12051325
Received: 13 April 2020 / Revised: 15 May 2020 / Accepted: 19 May 2020 / Published: 22 May 2020
(This article belongs to the Special Issue A Special Issue on Tumor Stroma )
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. View Full-Text
Keywords: hyaluronan; CD44; inflammation; tumor microenvironment; breast cancer hyaluronan; CD44; inflammation; tumor microenvironment; breast cancer
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Witschen, P.M.; Chaffee, T.S.; Brady, N.J.; Huggins, D.N.; Knutson, T.P.; LaRue, R.S.; Munro, S.A.; Tiegs, L.; McCarthy, J.B.; Nelson, A.C.; Schwertfeger, K.L. Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer. Cancers 2020, 12, 1325.

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