Stroma as an Active Player in the Development of the Tumor Microenvironment

Abstract

The stroma is a considerable part of the tumor microenvironment. Because of its complexity, it can influence both cancer and immune cells in their behavior and cross-talk. Aside from soluble products released by non-cancer and cancer cells, extracellular matrix components have been increasingly recognized as more than just minor players in the constitution, development and regulation of the tumor microenvironment. The variations in the connective scaffold architecture, induced by transforming growth factor beta, lysyl oxidase and metalloproteinase activity, create different conditions of ECM density and stiffness. They exert broad effects on immune cells (e.g. physical barriers, modulation by release of stored TGF-β1), mesenchymal cells (transition to myofibroblasts), epithelial cells (epithelial-to-mesenchymal transition), cancer cells (progression to metastatic phenotype) and stem cells (activation of differentiation addressed by the microenvironment characteristics). Physiological mechanisms of the wound healing process, as well as mechanisms of fibrosis in some chronic pathologies, closely recall aspects of cancer deregulated biology. Their elucidation can provide a better understanding of tumor microenvironment immunobiology. In the following short review, we will focus on some aspects of the fibrous stroma to highlight its active participation in the tumor microenvironment constitution, tumor progression and the local immunological network.

In VivoVisualization and Characterization of Epithelial–Mesenchymal Transition in Breast Tumors

“…Our results also point out that blood vessels are crucial to the spatial location and temporal migration of the EMT cells, suggesting that targeting blood vessel related factors might be beneficial in impeding EMT occurrence and restraining EMT cells’ behaviors. Blood vessels supply nutrients and growth factors that allow tumors to grow (22). A panel of growth factors, including TGF-β, EGF, FGF, hepatocyte growth factor (HGF), Insulin-like growth factor 1 (IGF-1), and platelet-derived growth factor (PDGF), was investigated in inducing the EMT-like morphological changes of the PyMT tumor-derived EMT cells; of these TGF-β and HGF provoked obvious loss of cell-cell contacts, which was not observed with other growth factors (16).…”

Comprehensive Computational Pathological Image Analysis Predicts Lung Cancer Prognosis

“…31,32 Pathological images harbor essential information on the histological organization and morphological characteristics of tumor cells and their surrounding tumor microenvironment, both of which affect tumor growth patterns and contribute to tumor prognosis. 33 However, this information is hard to distinguish and extract using only the human eye and brain. Therefore, systematic analyses of pathological images using computer algorithms could reveal hidden information in decoding tumor development and progression in lung cancer.…”

Breast tumor stroma: A driving force in the development of resistance to therapies

“…A heterogeneous population of stromal cells surround the tumor cells and their microenvironment . Fibroblasts, immune/inflammatory cells, endothelial or mesenchymal cells, adipocytes, and bone marrow‐derived stem cells reside in the tumor microenvironment, are embedded in an extracellular matrix (ECM), and are nourished by a vascular network . In addition to the confirmed role in the tumor initiation, progression, and metastasis, stromal cells are emerging as new research targets in the MDR field .…”

“…[9] Fibroblasts, immune/inflammatory cells, endothelial or mesenchymal cells, adipocytes, and bone marrow-derived stem cells reside in the tumor microenvironment, are embedded in an extracellular matrix (ECM), and are nourished by a vascular network. [10] In addition to the confirmed role in the tumor initiation, progression, and metastasis, stromal cells are emerging as new research targets in the MDR field. [11] It has been reported that the organization of stromal cells and the composition of ECM are involved in the generation of a significant drug concentration gradient, metabolic changes, and increased interstitial fluid pressure, all of which can significantly enhance the resistance of tumor cells to chemotherapeutics.…”