Estrogen-induced SDF-1α production promotes the progression of ER-negative breast cancer via the accumulation of MDSCs in the tumor microenvironment

Abstract

Estrogen plays a role in the processes of tumorigenesis, metastasis, and drug resistance in estrogen receptor (ER)-positive breast cancer (BC). Whether estrogen contributes to ER-negative BC is unclear. Here, we aimed to investigate whether estrogen could stimulate the secretion of stromal-derived factor-1 (SDF-1α) by cancer-associated fibroblasts (CAFs) to promote the progression of ER-negative BC. We transplanted ER-negative BC cells into ovariectomized mice, which was followed by continuous injection of estrogen, and found that estrogen promoted the tumorigenesis of BC. Furthermore, High levels of SDF-1α and tumor-infiltrating myeloid-derived suppressor cells (MDSCs) were detected in the estrogen treatment group. Estrogen stimulates secretion of SDF-1α by CAFs extracted from BC patients. Recombinant SDF-1α could recruit MDSCs isolated from bone marrow cells of mice. In addition, the co-culture of CAFs and MDSCs demonstrated that the recruitment of MDSCs was increased when CAFs were exposed to estrogen. Using AMD3100 to block the SDF-1α/CXCR4 axis or gemcitabine to delete MDSCs, we observed that both of these agents could neutralize the effect of estrogen on tumorigenesis. Together, these results suggest that estrogen may promote the progression of ER-negative BC by stimulating CAFs to secrete SDF-1α, which can recruit MDSCs to the tumor microenvironment to exert tumor-promoting effects.

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

“…All of the cell types included under the MSDC umbrella express ERs, making the estrogen pathway a possible regulator of activity within this compartment. In estrogen-insensitive ovarian cancer models, estrogen promoted tumor growth by mobilizing and enhancing the inhibitory capacity of ER expressing MDSCs while estrogen depletion had the opposite effects (134,135). Mechanistically, this occurs through estrogen induced STAT3 signaling in bone marrow precursors by transcriptional upregulation of JAK and SRC activity, culminating in increased MDSCs in tumor bearing mice.…”

Cancer‑associated fibroblasts regulate the biological behavior of cancer cells and stroma in gastric cancer (Review)

“…TMEs are heterogeneous in nature, containing a surrounding extracellular matrix (ECM) and several different types of cell including fibroblasts, endothelial cells, immune cells, local and bone marrow-derived stromal stem and progenitor cells (7). In the present review, the current knowledge of cancer-associated fibroblasts (CAFs), which are important components in the TME, are summarized in order to elucidate the exact function(s) of CAFs in the regulation of different biological behaviors which occur in GC progression (8)(9)(10)(11).…”

“…Several factors mediate the differentiation of CAFs, and certain markers, including α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) and platelet-derived growth factor (PDGF) receptor α/β, have been used to distinguish CAF from other types of fibroblast ( Fig. 1) (10,(13)(14)(15)).…”

Doxorubicin pretreatment enhances FAPα/survivin co-targeting DNA vaccine anti-tumor activity primarily through decreasing peripheral MDSCs in the 4T1 murine breast cancer model

“…FAPα + CAFs alter the extracellular matrix by secreting CXCL12, CCl2, collagen I, and other factors, which renders the TME suitable for tumor growth but not for tumorinfiltrating lymphocytes to destroy tumors, and prevents additional effector T cells from entering tumors. 14,15,40,41 Deleting FAPα + cells from tumors causes rapid hypoxic necrosis of tumors. 42 Additionally, studies by ourselves and others have shown that DNA vaccines targeting FAPα can alter the TME by inducing FAPα-specific CD8 + T cells to infiltrate into tumors and target FAPα + CAFs.…”

“…[10][11][12] Moreover, CAFs can also recruit myeloid-derived suppressor cells (MDSCs) to infiltrate into tumors by secreting CCL2 and CXCL12 to inhibit the anti-tumor immune responses. [13][14][15] In our previous work, we constructed a DNA vaccine targeting fibroblast activating protein α (FAPα), which expressed on the surface of CAFs. The DNA vaccine, OsF, could remodel the TME by inducing a large number of tumor-infiltrating lymphocytes to target FAPα-expressing CAFs.…”