SUSD2 promotes tumor-associated macrophage recruitment by increasing levels of MCP-1 in breast cancer

Abstract

Tumor-associated macrophages (TAMs) play a role in tumor angiogenesis and are recruited into the tumor microenvironment (TME) by secreted chemokines, including Monocyte Chemoattractant Protein-1 (MCP-1/CCL2). Angiogenesis is required to sustain proliferation and enable metastasis of breast cancer (BCa) cells. Understanding the underlying mechanisms of TAM recruitment would allow for the identification of desperately needed novel drug targets. Sushi Domain Containing 2 (SUSD2), a transmembrane protein on BCa cells, was previously shown to promote tumor angiogenesis in a murine model. To identify the role of SUSD2 in angiogenesis, 175 human breast tumors were surveyed by immunohistochemical analysis for the presence of SUSD2 and macrophages. Tumors with high levels of SUSD2 staining contained 2-fold more TAMs, mainly of the M2 pro-angiogenic phenotype. An in vitro co-culture model system was developed by differentiating SC monocytes into SC M0 macrophages. A 2-fold increase in polarized M2 macrophages was observed when M0 macrophages were incubated with SUSD2-expressing BCa cells compared to cancer cells that do not contain SUSD2. Since MCP-1 is known to recruit macrophages, levels of MCP-1 were compared between SUSD2-expressing MDA-MB-231 and MBA-MB-231-vector control cell lines. MCP-1 RNA, intracellular protein and secreted MCP-1 were all significantly increased compared to the vector control. Knockdown of SUSD2 in SKBR3 resulted in significantly decreased levels of secreted MCP-1. Consistently, increased levels of MCP-1 were observed in Susd2-expressing tumors generated from an in vivo isogeneic mouse model compared to the vector control tumors. Because SUSD2 recruits macrophages into the TME and promotes M2 polarization, inhibiting the function of SUSD2 may be an effective therapy for breast cancer patients.

Expression of sushi domain containing two reflects the malignant potential of gastric cancer

“…For example, SUSD2 increases the invasiveness of breast cancer cells and may act as a component of the mechanism of immune evasion through induction of apoptosis of the Jurkat T cell line . SUSD2 recruits macrophages into the tumor microenvironment, and promotes M2 polarization, indicating that inhibiting the function of SUSD2 may serve as an effective therapy for patients with breast cancer …”

“…14 SUSD2 recruits macrophages into the tumor microenvironment, and promotes M2 polarization, indicating that inhibiting the function of SUSD2 may serve as an effective therapy for patients with breast cancer. 16 In contrast, SUSD2 may act as a tumor suppressor. For example, SUSD2 exhibits tumor suppressor activity in highgrade serous ovarian carcinomas 17 and may function as a tumor suppressor in renal cell carcinoma and lung cancer.…”

Comparative proteomics of soluble factors secreted by human breast adipose tissue from tumor and normal breast

“…Surprisingly, we found a decrease of MCP-1 and MCP-2 in hATT-CMs compared to hATN-CMs. These two cytokines are involved in macrophage recruitment, and have been previously found to be increased in breast tumors [ 43 , 44 ]. Furthermore, it has been described that MCP-1 stromal levels correlate with the number of tumor-associated macrophages (TAMs), in a xenographic model of breast cancer [ 45 ].…”

Noninvasive detection of cancer spread to lymph nodes: A review of molecular imaging principles and protocols

“…EGFR in head and neck cancer and prostate‐specific membrane antigen in prostate cancer are good examples of targets that are overexpressed by a large percentage of tumor cells within their respective cancer types. In addition to the targets already mentioned for breast cancer, Sushi Domain Containing 2 is another promising target for breast cancer nodal imaging, which was recently found to be overexpressed in the breast cancers of 44 of 45 patients with lymph node metastases …”