The mutual interaction between tumor associated macrophages and cancer cells and its impact on pancreatic cancer stemness

Abstract

Pancreatic cancer (PC) is the fourth commonest cause of cancer-related mortality across the world with incidence equaling mortality The incidence of PC is gradually increased in Taiwan Surgery is the primary method to treat patients with PC but only 10% of the diagnosed patients can be treated by surgical resection These unresectable cases were divided into two groups on metastasis or locally advanced PC The five-year survival rate is less than 5% suggesting the limited in diagnosis and treatment of PC Recently reports illustrate tumor associated macrophages (TAMs) infiltration in tumor tissue and the existence of cancer stem cells (CSCs) may promote cancer cells proliferation invasion and metastasis Both TAMs and CSCs were associated with poor prognosis However the interaction between CSCs and TAMs and the way by which TAMs sustain CSCs mediates PC progression remains to be explored In this study we found that CD204-positive TAMs expression related with CD44 and CD133-positive CSCs in tissue microarray containing 96 clinical PC specimens and coexpression of CSCs and TAMs predicted poor prognosis Furthermore we established a coculture system of pancreatic cancer cells and monocytes to monitor how the interplay between CSCs and TAMs accelerates tumor development and progression The results showed that cancer cells induced TAMs activation via coculture TAMs promoted cancer stemness and tumorigenesis in vitro and in vivo On the basis of RNA microarray and cytokine array data we proposed the interplay between CSCs and TAMs was mediated by secreting MIF IL-8 and CCL5 We also verified these results by MetaCore quantitative real-time PCR and Western blot analysis and found that CSC growth was regulated in a paracrine manner by TAMs through MIF/IL-8/CCL5 axis; in particular the inhibition of MIF signaling using a specific inhibitor could suppress cancer stemness and tumour growth Importantly the induction of MIF IL-8 or CCL5 in response to coculture was abolished by NF-κB inhibitor BAY 11-7082 Finally we confirmed these findings in a cohort of 96 PC patients and determined the clinical significance of MIF/IL-8/CCL5 paracrine signaling on PC progression Taken together our results suggest that tumor microenvironment TAMs may play an important role in maintaining cancer stemness Simultaneous targeting cancer-derived MIF and TAMs is a new therapeutic strategy for PC

Date of Award	2015 Mar 23
Original language	English
Supervisor	Yan-Shen Shan (Supervisor)