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.
Highlights
Autologous fat graft is used as a filler for breast reconstruction in cancer patients following conservative surgery
To evaluate the role c-Met expression could have in predicting susceptibility of breast cancer cells to Adipose-derived Mesenchymal Stem Cells (ASCs), we evaluated expression levels of c-Met in primary breast cancer cells isolated from eleven human donors which were co-injected with autologous ASCs into immunocompromised mice to assess tumorigenicity
Based upon this evidence we investigated the role that ASCs could have in recurrence of breast cancer patients, undergoing autologous fat graft for breast reconstruction
Summary
Autologous fat graft is used as a filler for breast reconstruction in cancer patients following conservative surgery. Autolougous fat grafts were used to correct irregularities and, surprisingly they showed to promote a local tissue repair as a result of a new microenvironment, where ASCs favour healing processes [1], as it was shown for tissue damaged by radiotherapy in post-surgery breast cancer patients [2]. Inflammation contributes to metastasis favouring homing of disseminated tumor cells in new tissues [6]. This is feasible because breast tumor cells produce cytokines and growth factors, and express their cognate receptors which could be activated both in a paracrine and autocrine fashion [7]
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