Recently developed approaches for reshaping the pancreatic tumor stroma might be used in treatments for pancreatic cancer, according to a review in the March issue of Gastroenterology. The authors discuss relationships among the pancreatic tumor extracellular matrix, the vasculature, the immune system, and metabolism, and how these might be manipulated to stop pancreatic tumor progression.
Pancreatic tumors form a fibrotic stroma called desmoplastia, characterized by extensive deposition of extracellular matrix (ECM) components and localization and activation of cancer-associated fibroblasts, which reduces vasculature patency and drug access, and alters the anti-tumor immune response. This stroma promotes but can also prevent progression of pancreatic tumors, so there are mulitple factors to consider in designing therapeutics to target the tumor stroma.
Claire Vennin et al describe the tumor’s different stromal compartments and strategies for targeting or reshaping them. They explain how short-term manipulation of interactions between cancer cells and the stroma, in primary and metastatic sites (such as the liver), can improve the efficacy of chemotherapy and reduce growth of metastases, without disrupting normal tissue functions.
Vennin et al describe mechanical activation of signaling pathways that regulate survival and metastasis in pancreatic cancer cells, and ways to target the mechanical features of the tumor’s ECM. They provide a table of clinical trials of agents designed to disrupt the pancreatic tumor ECM.
The authors explain that tissue stiffening is also mediated by cell contractility, which is regulated by ROCK signaling. Levels of ROCK1 and ROCK2 increase in human pancreatic tumors with stage and grade, and genomic alterations that affect expression of these proteins correlate with shorter survival times of patients.
Survival and proliferative stimuli provided by the ECM are partly mediated by integrins and SRC signaling. SRC expression and activity are increased in human pancreatic ductal carcinomas, correlated with reduced survival time. A SRC inhibitor reduces migration and invasion of PDAC cell lines, and significantly inhibited development of metastases in mice with pancreatic tumors. Vennin et al summarize targets for slowing pancreatic tumor progression in a figure.
The fibrotic tumor stroma affects the immune response—pancreatic stellate cells and cancer-associated fiborblasta reduce T-cell infiltration of the tumor. Agents that inactivate pancretic stellate cells slow cancer cell proliferation and invasion in mice. Vennin et al explain how activated inactivate pancretic stellate cells also induce metabolic changes in cancer cells, such as secretion of non essential amino acids, which fuel the tricarboxylic acid cycle and mitochondrial proceses.
Models of stromal compartments are required to determine the efficacy of anti-stromal agents before clinical assessment. Vennin et al summarize the models that have been designed to study specific events in the stroma during pancreatic tumor progression. The authors also describe the potential applications and limitations of newly developed 3-dimensional tools for studying the tumor stroma and testing anti-stromal agents, such as 3D organoids.
Vennin et al conclude by stating that the pancreatic tumor stroma is heterogeneous, but biomarkers could help identify patients likely to benefit from agents that manipulate the stroma before and during treatment of pancreatic cancer.