Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells

Abstract

Pancreatic cancer (PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts (CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and non-cellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a context-dependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.

Epigenetic Control of the Tumor Microenvironment

“…Tumors typically contain a number of different stromal cell types, including fibroblasts, lymphocytes, macrophages and endothelial cells (see Figure 1) [1][2][3][4][5]. In some tumor types (e.g., pancreatic ductural adenocarcinoma [PDAC]), the number and mass of stromal cells in a tumor far exceeds that of the cancer cells [6,7].…”

“…These immune cells maintain the tumor microenvironment in a chronically inflammatory and immunosuppressive state [14]. Endothelial cells are recruited to form new blood vessels in the tumor by secretion of VEGF and other ligands from tumor cells and other cell types [4].…”

Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-paclitaxel Reduces the Number of Cancer-associated Fibroblasts Through Depletion of Pancreatic Stroma

“…Recent reports have suggested that targeting components of the desmoplastic reaction may enhance the activity of therapeutics targeting tumor cells (10,11). CAFs are the main effector cells in the desmoplastic reaction, pancreatic stellate cells being the most important source of CAFs (12). The lack of effective therapeutic options and the consequent high mortality rate of PDAC indicate the need to explore other treatment options, such as those aimed at reducing desmoplasia.…”

Evaluation of Inflammatory Cells (Tumor Infiltrating Lymphocytes) in Solid Tumors

“…Bohaté desmoplastické stroma předsta-vuje jednu ze základních charakteristik duktálního karcinomu pankreatu a řada studií potvrzuje, že role aktivovaného stromálního mikroprostředí má zásadní vliv na agresivitu tumoru a jeho odpověď na terapii [35,36]. Příznivý prognostický význam vysoké denzity TIL byl demonstrován pro několik jejich podtypů, především CD4+, CD8+ T lymfocyty a M1 intratumorální makrofágy [37].…”