Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

“…While gemcitabine is still considered as a first-line therapy and is given alone or combined with other agents to attack locally advanced or metastatic pancreatic cancers, the success is very limited and disappointing (5,6,8,47,48). The failure of gemcitabine to attack aggressive pancreatic cancers cells is due to intrinsic (metabolic malfunction) or extrinsic resistance (drug delivery/ desmoplasia) or both to gemcitabine (9,15,47). Thus, multiple studies have been carried out to understand the mechanism, and they gave new insights into the gemcitabine resistance of aggressive cancer cells having cancer stem cell-like properties (47,(49)(50)(51).…”

“…The failure of gemcitabine to attack aggressive pancreatic cancers cells is due to intrinsic (metabolic malfunction) or extrinsic resistance (drug delivery/ desmoplasia) or both to gemcitabine (9,15,47). Thus, multiple studies have been carried out to understand the mechanism, and they gave new insights into the gemcitabine resistance of aggressive cancer cells having cancer stem cell-like properties (47,(49)(50)(51). These studies, collectively, suggested that simultaneously targeting intrinsic-and extrinsic-resistant events may increase the toxic effects of gemcitabine and increase patient survival.…”

“…Despite some controversies (55), many patients with PDAC are resistant to gemcitabine because of desmoplasia, which is about 90% of the tumor volume and help in promoting intrinsic and extrinsic resistance to gemcitabine (47,49). One of the primary cellular compartments of desmoplasia is cancer cell-associated fibroblasts (CAF).…”

Pancreatic Stellate Cells Secrete Deoxycytidine Conferring Resistance to Gemcitabine in PDAC

“…Initially, the stiff stroma was thought to present a physical barrier to drug perfusion, however it is now appreciated that limiting drug delivery is not the only reason pancreatic tumors are therapy resistant (6)(7)(8). The ways in which the stromal cells within pancreatic cancer contribute to PDAC resistance has become an area of intense study, with a recent focus on interaction between stroma and PDAC via direct contact and paracrine signaling (9)(10)(11)(12). A variety of biomolecules secreted by pancreatic stromal cells have been implicated in resistance to radio-and chemotherapy, including cytokines such as SDF-1a and IGFs, extracellular matrix (ECM) proteins such as fibronectin and collagen I, and even exosomes (13)(14)(15)(16)(17).…”

“…In addition to the above methods, the stroma has also been shown to cause resistance by sequestering gemcitabine, a deoxycytidine (dC) analog (11,18). The mechanism by which gemcitabine causes toxicity in cells in well studied (19).…”