Programming of macrophages by apoptotic cancer cells inhibits cancer progression through exosomal PTEN and PPARγ ligands

Abstract

Apoptotic cell clearance by phagocytes is essential in tissue homeostasis. We demonstrated that conditioned medium (CM) from macrophages exposed to apoptotic cancer cells inhibits epithelial-mesenchymal transition (EMT), migration, and invasion of cancer cells with the acquisition of cancer-stem-like traits. Apoptotic 344SQ (ApoSQ) cell-induced PPAR{gamma} activity in macrophages caused increased PTEN levels, secreted in exosomes. ApoSQ-exposed CM from PTEN knockdown cells failed to enhance PTEN in recipient 344SQ cells, restore cellular polarity, and exert anti-EMT and anti-invasive effects. The CM which deficient of PPAR{gamma} ligands could not reverse the suppression of PPAR{gamma} activity and PTEN and consequently failed to the prevent EMT process. Moreover, single injection of ApoSQ cells inhibited lung metastasis in syngeneic mice with enhanced PPAR{gamma}/PTEN signaling both in tumor-associated macrophages and tumor cells. PPAR{gamma} antagonist GW9662 reversed PTEN signaling and anti-metastatic effect. Thus, apoptotic cancer cell therapy may offer a new strategy for the prevention of metastasis.