Pancreatic cancer stroma: an update on therapeutic targeting strategies.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the Western world with limited therapeutic options and dismal long-term survival. The neoplastic epithelium exists within a dense stroma, which is recognized as a critical mediator of disease progression through direct effects on cancer cells and indirect effects on the tumour immune microenvironment. The three dominant entities in the PDAC stroma are extracellular matrix (ECM), vasculature and cancer-associated fibroblasts (CAFs). The ECM can function as a barrier to effective drug delivery to PDAC cancer cells, and a multitude of strategies to target the ECM have been attempted in the past decade. The tumour vasculature is a complex system and, although multiple anti-angiogenesis agents have already failed late-stage clinical trials in PDAC, other vasculature-targeting approaches aimed at vessel normalization and tumour immunosensitization have shown promise in preclinical models. Lastly, PDAC CAFs participate in active cross-talk with cancer cells within the tumour microenvironment. The existence of intratumoural CAF heterogeneity represents a paradigm shift in PDAC CAF biology, with myofibroblastic and inflammatory CAF subtypes that likely make distinct contributions to PDAC progression. In this Review, we discuss our current understanding of the three principal constituents of PDAC stroma, their effect on the prevalent immune landscape and promising therapeutic targets within this compartment.

Critical role for D-type cyclins in cellular transformation induced by E6/E7 of human papillomavirus type 16 and E6/E7/ErbB-2 cooperation.

Recently, we reported that E6/E7 of human papillomavirus (HPV) type 16 cooperates with the ErbB-2 receptor to induce cellular transformation of human normal oral epithelial (NOE) and mouse normal embryonic fibroblast (NEF) cells. Furthermore, we demonstrated that cyclin D1 is essential for this transformation induced by E6/E7 and E6/E7/ErbB-2 cooperation using cyclin D1 antisense and knockout (D1(-/-)) cells. To determine the role of all D-type cyclins (D1, D2 and D3) in E6/E7/ErbB-2 cooperation, we examined the effects of E6/E7, ErbB-2 alone and E6/E7/ErbB-2 together in NEF, NEF-D1(-/-), NEF-D2(-/-) and NEF-D3(-/-) cells. We confirm that NEF-E6/E7 and NEF-E6/E7/ErbB-2, but not NEF-ErbB-2 cells, induce colony formation in soft agar and tumor formation in nude mice. We report that E6/E7, ErbB-2 and E6/E7/ErbB-2 together all fail to induce neoplastic transformation of D1(-/-) and D2(-/-) cells in vitro and in vivo. In contrast, E6/E7/ErbB-2 together but neither E6/E7 nor ErbB-2 alone provoke cellular transformation of D3(-/-) cells. Nevertheless, D3(-/-)E6/E7/ErbB-2 cells resulted in up to a 60 and 50% decrease in colony and tumor formation in soft agar and nude mice, respectively, compared with NEF-E6/E7/ErbB-2 cells. Furthermore, using cyclin D2 small interfering RNA we inhibited tumor and colony formation of the human NOE-E6/E7-ErbB-2-transformed cell line; in contrast, cyclin D3 small interfering RNA repressed approximately 50% of colony and 40% of tumor formation of E6/E7/ErbB-2 cooperation in this cell line. These data suggest that cyclins D1, D2 and D3 (to a lesser extent) are important downstream mediators of the cellular transformation induced by E6/E7 and E6/E7/ErbB-2 cooperation in normal cells. Our data imply that anti-D-type cyclin therapies are important in the treatment of human cancers expressing high-risk HPV or HPV/ErbB-2.