The critical roles of activated stellate cells-mediated paracrine signaling, metabolism and onco-immunology in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a “partner in crime” to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure. In addition to multiple paracrine signaling pathways, recent research has confirmed that PSCs-mediated tumor microenvironment may influence behaviors of PDAC via diverse mechanisms, such as rewiring metabolic networks, suppressing immune responses. These new activities are closely linked with treatment and prognosis of PDAC. In this review, we discuss the recent advances regarding new functions of activated PSCs, including PSCs-cancer cells interaction, mechanisms involved in immunosuppressive regulation, and metabolic reprogramming. It’s clear that these updated experimental or clinical studies of PSCs may provide a promising approach for PDAC treatment in the near future.

Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression

“…overcoming nutrient deprivation; and 3.) vast immunosuppression of anti-tumor immune cells (Fu et al, 2018;Ryan et al, 2014). Our results confirm that all three hallmarks are interconnected, and that NetG1 expression in CAFs is a central driver of the PDAC microenvironment.…”

“…In addition to the metabolic roles, CAFs are also at the center of the immunosuppressive PDAC microenvironment (Basso et al, 2014;Clark et al, 2007;Fu et al, 2018;Harper and Sainson, 2014). CAFs exert immunosuppressive effects through direct modulation of immune cell function via cytokine secretion (Wu et al, 2017), exclusion of anti-tumor immune cells from the tumor (Ene-Obong et al, 2013), and/or recruitment of immunosuppressive immune cells to the tumor (Kumar et al, 2017).…”

Bone metastasis as primary presentation of pancreatic ductal adenocarcinoma: A case report and literature review

“…10,11 The metastatic process is strictly connected to tumor intrinsic and extrinsic characteristics. 12 As in other several solid and hematologic cancer, [13][14][15] the tumor microenvironment emerged as a pivotal driver of metastatic niche 16 being correlated at the same time to cell-adhesion dependent and independent drug-resistance development. [17][18][19][20] Thus, several approaches have been envisioned in order to molecularly overcome this malignant phenotype, in order to target both the cancer cells and the tumoral milieu.…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…Beyond this "passive action, " aPSC/CAF contribute to the acquisition of major hallmarks of PaCa via cytokines, chemokines, growth factors, and their receptors that promote tumor cell proliferation and chemoresistance, accelerate intrapancreatic nerve invasion and distant metastatic growth and assist establishing an inflammatory milieu that forces immune destruction (482). aPSC/CAF supply essential nutrients and promote metabolic reprogramming backing tumor cell survival and proliferation (483), which is assisted by aPSC/CAF miRNA (484). These activities are briefly elaborated in the following sections.…”