Stromal reprogramming offers a novel therapeutic approach in pancreatic cancer (Implications of inhibiting the HGF-c-MET pathway in pancreatic cancer)

Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer related deaths with a 5-year survival rate as low as 5%. It is now acknowledged that the desmoplastic / stromal reaction, a characteristic feature of PC, contributes to progression of this cancer, by facilitating local growth and distant metastasis. Our laboratory was the first to demonstrate that pancreatic stellate cells (PSCs), i) produce the collagenous stroma of PC, and ii) interact closely with cancer cells to facilitate cancer progression. A candidate growth factor pathway that may mediate this PSC-cancer cell interaction is the hepatocyte growth factor (HGF) /c-MET (receptor for HGF) pathway.

This thesis studies the effects of inhibiting HGF and c-MET, in the presence and absence of chemotherapy, on PC progression using (i) an orthotopic model of PC (in vivo approach), and (ii) human PC cells (AsPC-1) and PSCs (hPSCs) in culture (in vitro approach).

My novel data have demonstrated that HGF inhibition (with neutralising antibody AMG102) as well as c-MET inhibition (using Compound A, a small molecule c-MET inhibitor), either singly or together were as effective as standard chemotherapy (gemcitabine) in inhibiting local tumour growth. Combining either HGF or c-MET inhibition with gemcitabine also reduced tumour growth. However, the combination of all three approaches (HGF inhibition + c-MET inhibition + chemotherapy) reduced tumour growth most, and more importantly, virtually eliminated metastasis. Another important observation was that gemcitabine treatment by itself failed to prevent metastasis, but instead, induced epithelial-mesenchymal transition and stemness (as assessed by increased expression of stem cell markers) in a sub-population of cancer cells.

In vitro studies demonstrated that hPSC secretions not only induce proliferation and migration, but also inhibit apoptosis of cancer cells. These effects were countered by pre-treatment of hPSC secretions with HGF inhibitor or c-MET inhibitor indicating a key role for the HGF/c-MET pathway in PSC-PC interactions.

The above findings suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC, which could be used with existing treatment modalities as a multi-pronged approach, to significantly improve the clinical outcome of patients with pancreatic cancer.