Stromal CCL2 Signaling Promotes Mammary Tumor Fibrosis through Recruitment of Myeloid-Lineage Cells

Abstract

Obesity is correlated with breast tumor desmoplasia, leading to diminished chemotherapy response and disease-free survival. Obesity causes chronic, macrophage-driven inflammation within breast tissue, initiated by chemokine ligand 2 (CCL2) signaling from adipose stromal cells. To understand how CCL2-induced inflammation alters breast tumor pathology, we transplanted oncogenically transformed human breast epithelial cells with breast stromal cells expressing CCL2 or empty vector into murine mammary glands and examined tumor formation and progression with time. As tumors developed, macrophages were rapidly recruited, followed by the emergence of cancer-associated fibroblasts (CAFs) and collagen deposition. Depletion of CD11b + myeloid lineage cells early in tumor formation reduced tumor growth, CAF numbers, and collagen deposition. CCL2 expression within developing tumors also enhanced recruitment of myeloid progenitor cells from the bone marrow into the tumor site. The myeloid progenitor cell population contained elevated numbers of fibrocytes, which exhibited platelet-derived growth factor receptor-alpha (PDGFRα)-dependent colony formation and growth in vitro. Together, these results suggest that chronic inflammation induced by CCL2 significantly enhances tumor growth and promotes the formation of a desmoplastic stroma through early recruitment of macrophages and fibrocytes into the tumor microenvironment. Fibrocytes may be a novel target in the tumor microenvironment to reduce tumor fibrosis and enhance treatment responses for obese breast cancer patients.

CCL2: An Important Mediator Between Tumor Cells and Host Cells in Tumor Microenvironment

“…Early recruitment of macrophages is correlated with cancer initiation, which includes formation of a favorable TME. CAF recruitment and fibrosis stroma formation in tumors are also dependent on macrophage recruitment ( 98 ). The role of fibroblasts in the early progression of ductal carcinoma in situ remains to be explored.…”

“…Infiltration of adipose stromal cells into in tumor tissue enhance CCL2 production, contributing to more recruitment of myeloid-lineage cells ( 98 ). Uchiyama et al.…”

Macrophages and Extracellular Matrix in Breast Cancer: Partners in Crime or Protective Allies?

“…Also, the overexpression of CCL2 by breast stromal cells transplanted into mouse mammary glands leads to enhanced TAM infiltration, concomitant with increased collagen expression. Both of these effects were ablated by depletion of CD11b expressing cells ( 30 ). These data suggest that tumors can manipulate the CCL2/CCR2 pathway to facilitate the infiltration of tumor prone collagen-producing macrophages.…”

Multi‑faceted role of cancer‑associated adipocytes in the tumor microenvironment (Review)

“…Furthermore, neutralization experiments using anti-IL-6 or CCL2 antibodies have demonstrated that the migration enhancing effect of CAA-conditioned media can be abolished ( 15 ). A recent study has determined that chronic inflammation induced by CCL2 can significantly promote tumor growth and connective tissue matrix formation via the early entry of macrophages and fibroblasts into the TME ( 137 ).…”