Abstract
After oncogenic transformation, tumor cells rewire their metabolism to obtain sufficient energy and biochemical building blocks for cell proliferation, even under hypoxic conditions. Glucose and glutamine become their major limiting nutritional demands. Instead of being autonomous, tumor cells change their immediate environment not only by their metabolites but also by mediators, such as juxtacrine cell contacts, chemokines and other cytokines. Thus, the tumor cells shape their microenvironment as well as induce resident cells, such as fibroblasts and endothelial cells (ECs), to support them. Fibroblasts differentiate into cancer-associated fibroblasts (CAFs), which produce a qualitatively and quantitatively different extracellular matrix (ECM). By their contractile power, they exert tensile forces onto this ECM, leading to increased intratumoral pressure. Moreover, along with enhanced cross-linkage of the ECM components, CAFs thus stiffen the ECM. Attracted by tumor cell- and CAF-secreted vascular endothelial growth factor (VEGF), ECs sprout from pre-existing blood vessels during tumor-induced angiogenesis. Tumor vessels are distinct from EC-lined vessels, because tumor cells integrate into the endothelium or even mimic and replace it in vasculogenic mimicry (VM) vessels. Not only the VM vessels but also the characteristically malformed EC-lined tumor vessels are typical for tumor tissue and may represent promising targets in cancer therapy.
Highlights
In the last few decades, tumor therapy has made appreciable progress
This study showed that endothelial cells (ECs) are a possible source for cancer-associated fibroblasts (CAFs) in the microenvironment of angiogenic tumors
Tumor cells isolated from malignant pleural effusions, which develop in various malignancies due to impaired fluid drainage by blood or lymphatic vessels, inflammation and increased vascular permeability and are routinely drained for diagnosis, have been employed to test vasculogenic mimicry (VM) tube formation in vitro
Summary
In the last few decades, tumor therapy has made appreciable progress. In addition to surgical intervention, radio- and chemotherapy have significantly increased survival of tumor patients. While the oncogenically transformed tumor cell has been and will continue to be the focus of cancer therapy, an increasing number of publications in recent years has shed light on cells in the vicinity of tumor cells and their role in tumor progression. Endothelial cells (ECs) and immune cells belong to this cellular environment They are not unaffected bystanders, but their behavior changes in response to neighboring tumor cells. They may support growth and progression of cancer cells which eventually subvert the resident cells. This review highlights metabolic alterations and intercellular communication of tumor cells and their neighboring stromal fibroblasts and ECs. In addition, immune cells, such as macrophages, granulocytes, and leukocytes, are affected in a solid tumor and in turn affect tumor growth. This review focuses on fibrotic and vascular phenomena within growing solid tumor tissue
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