Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.

The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

“…Tumor ECM not only serves as a simple structural support but also plays a pivotal role in modifying tumor cell behavior. For example, aberrant ECM accumulation attributes to increased interstitial pressure and the collapse of capillary vessels, leading to the decreased delivery of blood flow and therapeutic agents, which results in a hypoxic microenvironment and altered drug response [47][48][49]. Signaling pathways, such as the integrin signaling pathway, also contribute to the regulation of cellular machinery in pancreatic cancer cells [50].…”

“…Among the stromal cell-derived ECM molecules, collagens are the predominant components, accounting for more than 90% of ECM proteins in pancreatic cancer stroma and chronic pancreatitis [45]. Collagens include 29 known superfamily members in vertebrates [49]. Proteomic analyses have revealed that approximately 90% of the total collagens in PDAC tissues are type I and type III fibrillar-type collagens [45], which are predominantly produced by stromal cells, especially ACTA2, the HUGO (Human Genome Organization)approved official symbol for actin alpha 2, smooth muscle; HGNC ID: 130; it is also known as alpha smooth muscle actin or αSMA-expressing fibroblasts [53].…”

Rac rather than Rho drives the early transcriptional response to extracellular matrix stiffness and mediates repression of ATF3

“…Increased tissue stiffness, typically a result of ECM remodeling, is seen in many pathological microenvironments, such as breast and pancreatic tumors, lung and liver fibrosis, and cardiovascular disease [26,[69][70][71][72][73][74][75][76][77][78] and has even been considered as a prognostic factor in cancer progression [79,80]. Our data indicate that ATF3 is an early and major transcriptional target of increased ECM stiffness.…”

Cold Atmospheric Plasma Does Not Affect Stellate Cells Phenotype in Pancreatic Cancer Tissue in Ovo

“…We have focused this study on the effect of CAP in PSCs because the stroma regulates the molecular interactions with the ECM, is responsible for the remodelling of the TME in PDAC, and facilitates the invasion and metastasis of cancer cells [46]. The matrix metalloproteinases (MMPs), mostly secreted by PSCs, but also by PDAC cells, participate actively in this process [47].…”