Targeting desmoplasia in pancreatic cancer as an essential first step to effective therapy

Abstract

Pancreatic cancer is considered one of the most lethal cancers in the US. It contributes to an estimated 47,000 deaths annually and is predicted to surpass prostate, breast and colorectal cancers as the leading cause of cancer-related death. Although major advancements in cancer treatment have improved outcomes for many cancer types, survival rate for pancreatic cancer has not improved in nearly four decades despite tremendous effort. One attribute of pancreatic cancer that is considered a major barrier to effective treatment is the formation of fibrotic tissue around tumor cells known as desmoplasia. A number of promising approaches have been developed to deplete fibrotic components in pancreatic tumors to enhance drug delivery, some of which have been tested in clinical trials of advanced, unresectable pancreatic cancer. Here, we discuss previous efforts, shortcomings and new considerations for developing more effective agents to eliminate desmoplasia.

Keywords: collagen; desmoplasia; fibrosis; hyaluronan; pancreatic cancer.

Figure 1. Desmoplasia is a major hallmark of PDAC.

Desmoplasia, or the desmoplastic reaction, is characterized by the prevalent growth of dense fibrotic tissue around tumor cells. Activated stromal cells (fibroblasts, myofibroblasts, stellate cells) and, in some cases, tumor cells overexpress various extracellular matrix (ECM) components (hyaluronan, collagen, SPARC, α-SMA, tenascin C) that contribute to fibrosis. Hyaluronan and collagen (predominantly types I and IV) contribute to the bulk of interstitial forces that leads to blood vessel compression, while also acting as ligands for immune suppressive signaling in T and NK cells. Constant remodeling of the tumor stroma, involving breakdown and synthesis of ECM components, also facilitates distal metastasis. Overall, the presence of desmoplasia in PDAC impedes anti-cancer drug efficacy leading to treatment failure and, thus, serves as an important target that should be eliminated prior to therapy.