Pancreatic cancer–associated stroma production

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Abstract

One of the defining features of pancreatic ductal adenocarcinoma (PDAC) is the presence of extensive desmoplasia. The desmoplastic stroma consists of proliferating fibroblasts and pancreatic stellate cells that produce and deposit fibronectin and collagens, inflammatory cells and macrophages that produce chemokines and cyokines, nerve fibers that release nerve growth factors, and marrow-derived stem cells. Stroma production is facilitated by the abundance of growth factors, including fibroblast growth factors (FGFs), epidermal growth factor (EGF) receptor ligands, transforming growth factor–β (TGF-β) isoforms, and connective tissue growth factor. Due to its location in the pancreas, stromal cells and pancreatic cancer cells are also exposed to high insulin levels. The stromal compartment stores and synthesizes multiple growth factors and the heparan sulfate proteoglycans glypican-1 and syndecan-1. This unique microenvironment harbors and nourishes the cancer cells, facilitating their invasive and metastatic potential. Targeting the stroma may thus provide novel therapeutic options in this deadly malignancy.

Section snippets

Molecular Aspects of Pancreatic Cancer

PDAC is known to overexpress many mitogenic growth factors and their corresponding high-affinity tyrosine kinase receptors [7], and to harbor a high frequency of mutations in the K-ras oncogene, the p53 and Smad4 tumor-suppressor genes, and the p16 cell cycle inhibitory gene [8]. In addition, there is excessive activation of downstream signaling pathways, such as the src, nuclear factor κB (NFκB), and Stat3 signaling pathways [9], [10], [11]. Together, these alterations enhance cancer cell

Origin of Pancreatic Cancer and Its Associated Stroma

The exact cell type that gives rise to PDAC is not known. In theory, PDAC may arise from a poorly differentiated ductal cell, a de-differentiated acinar or islet cell, a progenitor cell, or a stem cell. In recent years there has been a growing appreciation that pancreatic intraepithelial neoplasias (PanINs) constitute precancerous lesions that lead to PDAC [12], [13]. Low-grade lesions are termed PanIN-IA and PanIN-1B, and these lesions often harbor activating K-ras mutations.

Potential Role of Stroma in Pancreatic Cancer: Invasion and Metastasis

Several types of tumor–stroma interactions have been implicated as having the potential to promote pancreatic cancer cell invasion and metastasis. Cancer cell–derived growth factors, such as fibroblast growth factors (FGFs), transforming growth factor–β (TGF-βs), insulin-like growth factor-1 (IGF-1), and platelet-derived growth factor BB (PDGF-BB), become sequestered within the stroma, which thus acts as a storage site for these factors. The invading cancer cells produce matrix

Stroma-Targeted Therapeutics

The conclusion that the stroma and aberrant stromal–epithelial interactions contribute to pancreatic cancer spread and metastasis raises the possibility that targeting the stroma may represent an additional approach for treating pancreatic cancer. In this regard, any agents that target pro-fibrotic growth factors, such as small molecule tyrosine kinase inhibitors that interfere with epidermal growth factor (EGF) receptor, FGF receptor, PDGF receptor, or IGF-1 receptor signaling, may be useful

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    Supported by a grant from the National Cancer Institute (CA-75059).

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