The role of human bone marrow mesenchymal stromal cells in pancreatic cancer growth

Pancreatic cancer is one of the most lethal cancers characterized by local invasiveness, early metastasis, recurrence and high resistance to current therapies. Extensive stroma or desmoplasia is a key histological feature of the disease. Interactions between pancreatic cancer cells and tumor stroma are critical for pancreatic cancer development and progression. Mesenchymal stromal cells (MSC) are multipotent stromal progenitors that exhibit preferential tropism to primary and metastatic tumor sites. While MSCs represent a potential source of pancreatic cancer stroma, their contribution to pancreatic tumor growth remains poorly known. Here, we show that bone marrow MSC (BM-MSC) significantly contribute to pancreatic cancer growth in vitro and in vivo. Furthermore, MSC create a pro-carcinogenic microenvironment through the release of key factors mediating growth and angiogenesis including IL-6 and VEGF, and activation of STAT3 signaling in tumor cells. IL-6 released by MSC was mainly responsible for the pro-tumorigenic effects of MSC. In fact, knockdown of IL-6 expression in MSCs by small interference RNA (siRNA) abolished MSC-growth promoting effect in vitro reducing tumor cell proliferation and clonogenic potential. In addition, blocking of IL-6 classic- and trans-signaling by anti-IL-6 receptor antibody Tocilizumab or IL-6 trans-signaling by transfusion protein sgp130Fc in a heterotopic nude mouse model of human BxPc3 xenografts abrogated MSC mediated tumor-promoting effects delaying tumor formation significantly. In addition, Tocilizumab inhibited cancer growth remarkably resulting in smaller tumors compared to MSC control groups and tumor alone group. Moreover, anti-IL-6 therapy inhibited the profibrogenic effects of MSC leading to a significant reduction in tumor fibrosis in comparison to MSC control groups. Our data demonstrate that IL-6 produced by stromal cells plays a pivotal role in pancreatic cancer growth and is a new potential therapeutic target for patients with pancreatic cancer.Ph.D