American Association for Cancer Research
mcr-22-0872_supplementary_figure_2_suppsf2.pdf (72.03 kB)

Supplementary Figure 2 from Tumor-Derived CCL5 Recruits Cancer-Associated Fibroblasts and Promotes Tumor Cell Proliferation in Esophageal Squamous Cell Carcinoma

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journal contribution
posted on 2023-07-05, 08:42 authored by Karen J. Dunbar, Tatiana A. Karakasheva, Qiaosi Tang, Gizem Efe, Eric W. Lin, Michael Harris, Varun Sahu, Uma M. Sachdeva, Jianhua Hu, Andres J. Klein-Szanto, Brian Henick, J. Alan Diehl, Hiroshi Nakagawa, Anil K. Rustgi

Loss of tumor-derived CCL5 reduces tumor cell proliferation in TE-1 cells.


National Cancer Institute (NCI)

United States Department of Health and Human Services

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Cancer-associated fibroblasts (CAF) can promote tumor growth, metastasis, and therapeutic resistance in esophageal squamous cell carcinoma (ESCC), but the mechanisms of action remain elusive. Our objective was to identify secreted factor(s) that mediate the communication between CAFs and ESCC tumor cells with the aim of identifying potential druggable targets. Through unbiased cytokine arrays, we have identified CC motif chemokine ligand 5 (CCL5) as a secreted factor that is increased upon co-culture of ESCC cells and CAFs, which we replicated in esophageal adenocarcinoma (EAC) with CAFs. Loss of tumor-cell-derived CCL5 reduces ESCC cell proliferation in vitro and in vivo and we propose this is mediated, in part, by a reduction in ERK1/2 signaling. Loss of tumor-derived CCL5 reduces the percentage of CAFs recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists, namely Maraviroc. Maraviroc treatment reduced tumor volume, CAF recruitment, and ERK1/2 signaling in vivo, thus, mimicking the effects observed with genetic loss of CCL5. High CCL5 or CCR5 expression is associated with worse prognosis in low-grade esophageal carcinomas. These data highlight the role of CCL5 in tumorigenesis and the therapeutic potential of targeting the CCL5–CCR5 axis in ESCC.

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