Deciphering the role of stroma in pancreatic cancer

Abstract

Purpose of review This review intends to describe recent studies on pancreatic tumor associated stroma and potential opportunities and limitations to its targeting. Recent findings One of the defining features of pancreatic cancer is extensive desmoplasia, or an inflammatory, fibrotic reaction. Carcinoma cells live in this complex microenvironment which is comprised of extracellular matrix (ECM), diffusible growth factors, cytokines and a variety of non-epithelial cell types including endothelial cells, immune cells, fibroblasts, myofibroblasts and stellate cells. In addition to the heterogeneity noted in the non-neoplastic cells within the tumor microenvironment, it has also been recognized that neoplastic cancer cells themselves are heterogeneous, and include a subpopulation of stem-cell like cells within tumors termed cancer stem cells. Due to the failure of current therapeutics to improve outcomes in patients with pancreatic cancer, new therapeutic avenues targeting different components of the tumor microenvironment are being investigated. In this review article, we will focus on recent studies regarding the function of the tumor stroma in pancreatic cancer and therapeutic treatments that are being advanced to target the stroma as a critical part of tumor management. Summary Recent studies have shed new light on the contribution of the pancreatic cancer fibroinflammatory stroma to pancreatic cancer biology. Additional studies are needed to better define its full contribution to tumor behavior and how to best understand the optimal ways to develop therapies that counteract its pro-neoplastic properties.

STAT3 down regulates LC3 to inhibit autophagy and pancreatic cancer cell growth

“…The majority of patients must be treated with chemotherapy, which can lead to therapeutic resistance and an overall median survival of < 6 months. The lack of effective treatment options, late stage diagnosis and development of therapeutic resistance results in a dismal 5-year survival rate of approximately 5% and this has remained stable for several decades [20, 21]. Much evidence shows that the development of therapeutic resistance is due to elevated levels of oxidative stress in tumor cells and deregulation of multiple tumor cell survival signaling pathways including autophagy [22, 23].…”

State of the art and future directions of pancreatic ductal adenocarcinoma therapy

“…These are defined by the expression of stem cell markers (CD90, CD49a, CD73, and CD44), the functional capacity to differentiate into bone, cartilage, and adipose cells, and clonogenic ability (Waghray et al, 2014). These cells have been recently identified in the PanIN and PDAC stroma and demonstrated to have tumor-promoting properties, enhancing primary tumor growth and metastasis (Waghray, Yalamanchili, di Magliano, & Simeone, 2013). MSC have been shown to regulate the recruitment of macrophages in other cancer types.…”

Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises

“…In turn, CAFs' biology is positively regulated by PDA cells (43). The stromal cells were found in preclinical studies to impede the penetration of anti-cancer drugs resulting in inadequate cell kills (11,12). Hh signaling was implicated as a key regulator of tumor-stromal interaction in PDA (13 resulting in better cytotoxic effect.…”