Tissue-resident stem cells promote breast cancer growth and metastasis

Abstract

Mesenchymal stem cells derived from bone marrow have recently been described to localize to breast carcinomas and to integrate into the tumor-associated stroma. In the present study, we investigated whether adipose tissue-derived stem cells (ASCs) could play a role in tumor growth and invasion. Compared with bone marrow-derived cells, ASCs as tissue-resident stem cells are locally adjacent to breast cancer cells and may interact with tumor cells directly. Here, we demonstrate that ASCs cause the cancer to grow significantly faster when added to a murine breast cancer 4T1 cell line. We further show that breast cancer cells enhance the secretion of stromal cell-derived factor-1 from ASCs, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. The tumor-promoting effect of ASCs was abolished by knockdown of the chemokine C-X-C receptor 4 in 4T1 tumor cells. We demonstrated that ASCs home to tumor site and promote tumor growth not only when co-injected locally but also when injected intravenously. Furthermore, we demonstrated that ASCs incorporate into tumor vessels and differentiate into endothelial cells. The tumor-promoting effect of tissue-resident stem cells was also tested and validated using a human breast cancer line MDA-MB-231 cells and human adipose tissue-derived stem cells. Our findings indicate that the interaction of local tissue-resident stem cells with tumor stem cells plays an important role in tumor growth and metastasis.

Mesenchymal stem cells in mammary adipose tissue stimulate progression of breast cancer resembling the basal-type

“…Our observation that bMSCs assemble into vessel-like structures within Matrigel in vitro and in vivo, suggest that perhaps bMSC promote tumor vascularity by a second (and not necessarily mutually exclusive) mechanism: rather than recruiting endothelial cells to the tumor microenvironment, they incorporate into vessels within the tumor by directly differentiating into endothelial cells, as previously reported for adipose MSCs in an ischemic injury model [34][35][36] and the 4T1 murine model of breast cancer progression. 23 Despite our in vitro data favoring the potential involvement of bMSCs in promoting breast cancer vascularity, we did not observe a significant difference in capillary density either within or around the tumor when comparing T4-2 vs. T4-2/bMSC xenografts at two (fat pad and subcutaneous) inoculation sites. The precise molecular mechanism triggering the formation of cancer-associated blood vessels is unclear; however, hypoxia appears to be a critical mediator.…”

“…3,19 Experimental data demonstrate that MSCs from bone marrow and adipose tissue can efficiently home to tumors, including breast cancer, [20][21][22] where they can stimulate breast cancer growth and invasion, 20,[23][24][25] modulate inflammatory cells within the tumor microenvironment, 26 and give rise to carcinoma-associated fibroblasts. 10,27,28 But only recently have investigations focused on the role of local adipose MSCs on the progression of breast cancer.…”

Concise Review: Adipose-Derived Stromal Vascular Fraction Cells and Stem Cells: Let's Not Get Lost in Translation

“…The adipose-derived cell's immunomodulatory and immunosuppressive properties present additional concerns. Recent reports document the ability of ASCs to promote the proliferation of active breast cancer cells in vitro and in vivo via paracrine mechanisms [38][39][40][41][42]. Comparable studies indicate that ASCs promote the growth of prostate cancer cell lines transplanted into immunodeficient mice [43].…”

Adipose tissue-derived stem cells show considerable promise for regenerative medicine applications

“…Lately, scientific journals have been reporting that after topical and intravenous application, mouse ADSCs gathered in the growing neoplasm and promoted its uncontrolled in vivo growth [33]. Stimulation of carcinogenesis may be caused by factors secreted by ADSCs, such as stromal cell-derived factor (SDF-1), chemokine C-C-motif (CCL5) and transforming growth factor-β (TGFβ) [8].…”