Impact of the secretome of activated pancreatic stellate cells on growth and differentiation of pancreatic tumour cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) exists in a complex desmoplastic microenvironment. As part of it, pancreatic stellate cells (PSCs) provide a fibrotic niche, stimulated by a dynamic communication between activated PSCs and tumour cells. Investigating how PSCs contribute to tumour development and for identifying proteins that the cells secrete during cancer progression, we studied by means of complex antibody microarrays the secretome of activated PSCs. A large number of secretome proteins were associated with cancer-related functions, such as cell apoptosis, cellular growth, proliferation and metastasis. Their effect on tumour cells could be confirmed by growing tumour cells in medium conditioned with activated PSC secretome. Analyses of the tumour cells’ proteome and mRNA revealed a strong inhibition of tumour cell apoptosis, but promotion of proliferation and migration. Many cellular proteins that exhibited variations were found to be under the regulatory control of eukaryotic translation initiation factor 4E (eIF4E), whose expression was triggered in tumour cells grown in the secretome of activated PSCs. Inhibition by an eIF4E siRNA blocked the effect, inhibiting tumour cell growth in vitro . Our findings show that activated PSCs acquire a pro-inflammatory phenotype and secret proteins that stimulate pancreatic cancer growth in an eIF4E-dependent manner, providing further insight into the role of stromal cells in pancreatic carcinogenesis and cancer progression.

Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer

“…Vonlaufen, Hwang, and Gao et al demonstrated that the cell supernatant of activated PSCs induced cancer cells proliferation and migration mediated by PDGF and SDF-1/CXCR [4,8,10]. It also found that PSCs significantly promoted the growth and metastasis of cancer cells by co-culturing PSCs Ivyspring International Publisher with pancreatic cancer cells [11,12]. Apte et al discovered that PSCs can induce tumor-promoting paracrine effects [13].…”

TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation

“…TGF-β signalling is also one of the most important features forming the CSC niche and promotes plasticity in PDAC [6]. The pancreatic stellate cells (PSC) within the tumour microenvironment represent the principal source of TGF-β1 [7,8], but still very little is known about the TGF-β1-mediated crosstalk between PSC and PDAC cells. While L1 cell adhesion molecule (L1CAM; CD171) was originally discovered in the nervous system due to its important function for axon guidance and cell migration [9][10][11][12][13][14][15], it has also been shown to be a crucial factor for tumour cell dissemination and metastasis in colorectal, breast, kidney and lung cancer [16,17].…”

Establishment and Characterization of Paired Primary Cultures of Human Pancreatic Cancer Cells and Stellate Cells Derived from the Same Tumor

“…Several recent reports have studied the complex interactions between PSCs and cancer cells based on analysis of their secretomes [42,60,61]. This prompted us to investigate the composition of the secretome from the paired primary PCCs and PSCs by proteomics-based analysis.…”

“…The high variability in migration induction by the various PSCs may reflect intertumoral heterogeneity. Several proteins secreted by PSCs including cytokines, growth factors, and ECM components are known to interact with the PCCs and to induce activation of various signaling pathways that lead to enhanced migration and proliferation of the cancer cells [19,25,41,42,63]. The secretome data from both PSCs and PCCs investigated for these proteins revealed that the extent of migration observed among various PCCs was directly proportional to the amount of ligands/substrate proteins secreted by PSCs as well as to the amount of receptor proteins from PCCs.…”

“…-5, and -6, respectively ( Figure 5B, Supplementary Materials Figure S5). The secretome data from the five paired PCCs and PSCs was further examined for proteins deemed to be involved in the regulation of migration of cancer cells [25,41,42]. Secretome analysis revealed significant intertumoral variability with respect to protein secretion in both PSCs and PCCs, as indicated in Figure 5C,D.…”