Adipose-derived mesenchymal stem cells (ASCs) may favour breast cancer recurrence via HGF/c-Met signaling

Abstract

Adipose tissue is a reservoir of Mesenchymal Stem Cells (Adipose-derived Mesenchymal Stem Cells, ASCs), endowed with regenerative properties. Fat graft was proposed for breast reconstruction in post-surgery cancer patients achieving good aesthetic results and tissues regeneration. However, recent findings highlight a potential tumorigenic role that ASCs may have in cancer recurrence, raising some concerns about their safety in clinical application.To address this issue, we established a model where autologous ASCs were combined with primary normal or cancer cells from breast of human donors, in order to evaluate potential effects of their interactions, in vitro and in vivo.Surprisingly, we found that ASCs are not tumorigenic per sè, as they are not able to induce a neoplastic transformation of normal mammary cells, however they could exhacerbate tumorigenic behaviour of c-Met-expressing breast cancer cells, creating an inflammatory microenvironment which sustained tumor growth and angiogenesis.Pharmacological c-Met inhibition showed that a HGF/c-Met crosstalk between ASCs and breast cancer cells enhanced tumor cells migration, acquiring a metastatic signature, and sustained tumor self-renewal.The master role of HGF/c-Met pathway in cancer recurrence was further confirmed by c-Met immunostaining in primary breast cancer from human donors, revealing a strong positivity in patients displaying a recurrent pathology after fat grafts and a weak/moderate staining in patients without signs of recurrence.Altogether our findings, for the first time, suggest c-Met expression, as predictive to evaluate risk of cancer recurrence after autologous fat graft in post-surgery breast cancer patients, increasing the safety of fat graft in clinical application.

Adipose-Derived Stems Cells and Their Role in Human Cancer Development, Growth, Progression, and Metastasis: A Systematic Review

“…Other authors have reported that ASCs may be protective, particularly in suppressing tumor growth and stimulating apoptosis. Most of the articles reviewed consistently pointed out that the role of ASCs in tumor development is complex, and that the tumor microenvironment milieu in which ASCs are present and the mechanisms by which they migrate may influence their role in cancer development (41)(42)(43)(44)(45).…”

“…Several mechanisms linking ASCs and tumor development/ progression have been described, with many studies highlighting the importance of tumor environment modification by ASCs (41)(42)(43)(44). ASCs may play a role in the creation of an inflammatory tumor microenvironment, which promotes tumorigenic activity.…”

“…ASCs may play a role in the creation of an inflammatory tumor microenvironment, which promotes tumorigenic activity. Eterno and colleagues (44) suggested that ASCs may worsen tumorigenic behavior of c-Met producing breast cancer cells by creating a tumor microenvironment characterized by inflammation. The TGFb1 signaling pathway may also play a role in the way ASCs interact with the tumor microenvironment (41).…”

Effect of adipose-derived stem cell-conditioned medium on the proliferation and migration of B16 melanoma cells

“…For example, when ASCs were co-injected with tumor cells, they promoted the tumorigenic growth of H460 human non-small cell lung cancer cells and U87MG malignant glioma cells in nude mice (5). A similar tumorigenic effect was observed in human prostate (6) and breast (7) cancer cells in mice. Furthermore, co-culture of ASCs enhanced the proliferation of human squamous cell carcinoma cells (8) and the migration of breast cancer cells in a xenograft model (9).…”

Research progress on the safety of cell-assisted lipotransfer in breast repairs after breast conserving therapy

“…These evidences showed communication between T47D and stem cells. Eterno et al indicated that the expression of HGF/c-Met signal may indicate breast cancer recurrence [28] . The study found that fat stem cells did not directly induce normal breast cells to become cancer cells but instead provided appropriate inflammatory microenvironment for the growth and vascularization of cancer cells by increasing the occurrence of tumorigenic behavior of breast cells.…”