Intercellular Interactions in the Tumor Stroma and Their Role in Oncogenesis

Abstract—Cancer remains the second leading cause of death in the world, despite significant improvements that have been made in diagnosis and therapy. This is partly due to the fact that most of the therapeutic agents that have been developed target tumor cells and ignore the tumor microenvironment. Currently, there is an increased interest in understanding the role of the microenvironment in tumor growth and progression, which has prompted a new paradigm of cancer treatment: targeting the tumor stroma. The stroma can make up more than 50% of the tumor node mass and coordinate proliferation, local invasion, and eventually metastasis of cancer cells into surrounding tissues. The stroma includes an extracellular matrix, immune cells, tumor vascular network, fibroblasts, neuroendocrine cells, and fat cells. Malignant cells recruit stromal cells to remodel the tissue structure and isolate growth stimuli and intermediate metabolites. As a result, stromal components contribute to multiple processes of oncogenesis, which include tumor growth, invasion, metastasis, and resistance to therapy. Cancer-associated fibroblasts play an important role in these processes. This review examines the main mechanisms of intercellular interactions in the tumor stroma, including their regulation and role in oncogenesis.