In living tissues, cells respond to multiple physical and biochemical cues which are established by the local cellular microenvironment [1]. Inside a tumor, tumor cells are surrounded by a highly modified stroma known as the tumor microenvironment or TME. In this microenvironment, cell-cell interactions, cell-extracellular matrix interactions, and factors released by both, cancer and stromal cells, are critical for tumor growth and development. Through these complex interactions, tumor microenvironment can affect gene expression, cell metabolism, chromatin structure, cell proliferation and cell migration [2]. The following video summarizes some interactions in the TME.

The main components of the TME are: vascular networks, the extracellular matrix, and cells.

Vascular Networks: The formation of a highly vascularized environment facilitates tumor progression by providing nutrients and additional factors secreted in the tumor microenvironment. Tumor angiogenesis occurs through the secretion of VEGF (Vascular Endothelial Growth Factor, see below), by cancer cells, fibroblasts, and stromal immune cells. This vascularization process surrounding tumors is abnormal regarding its arrangement and vessel composition. Vessels are leaky, which generates high interstitial pressures and an accumulation of molecules in the bloodstream [4]. Additionally, vascularization contributes to hypoxia. The link between abnormal vascular networks and hypoxia in the tumor microenvironment is further described in the Scientific Note Cancer and Hypoxia.

The Extracellular Matrix (ECM) is composed of extracellular proteins and proteoglycans, like collagen, laminin, elastin, fibrinogen, fibronectin, and vitronectin. The following video summarizes the function and composition of the ECM in healthy tissues:

In tumor cells, the ECM is highly remodeled through extracellular factors released by different cell types in the TME, including cancer cells. In the TME, cell contacts with the extracellular matrix activate signaling pathways like anti-apoptotic pathways. Interactions of cancer cells with the ECM can induce drug resistance in a process termed CAM-DR (cell adhesion mediated drug resistance) [3] [5]. Some extracellular signaling factors released in the ECM are (reviewed in [4]):

-TGF-β (Transforming Growth Factor β): In normal tissues TGF- β is a growth inhibitor, regulating tissue homeostasis and apoptosis and an immune system suppressor. However, TGF-β has proliferative effects on cancer cells and plays a key role in the epithelial to mesenchymal transition (EMT) (see below).

-SDF-1 (stromal cell-derived factor): A gradient of SDF-1 secreted by stromal cells is generated in the ECM and it contributes to the recruitment of cancer cells expressing a receptor for it, through chemotaxis. Ligand-receptor interactions induce cell migration and proliferation.

-HIF: It is a family of transcription factors activated upon hypoxia, which are involved in metabolism, angiogenesis, proliferation, and ECM remodeling in response to hypoxia [5].

-VEGF (Vascular Endothelial Growth Factor). It is mainly secreted by fibroblasts (CAFs, cancer-associated fibroblasts), but also cancer cells and immune cells. As a vascular growth factor, it is a major contributor of the abnormal angiogenesis occurring at the TME. It has also a role in extracellular matrix remodeling.

-SPARC (secreted protein acidic rich in cysteine), or osteonectin. Secreted in the stroma by fibroblasts and together with a role in proliferation and angiogenesis, it has a direct function on remodeling the extracellular matrix [4].

-Matrix Metallo Proteinases (MMPs): Secreted by fibroblasts and other stromal cell types, they have a function in hydrolysis of proteins in the extracellular matrix, like collagen or laminin, or cleavage of cytokines. This direct modification of the ECM has an impact on the ability of cancer cells to invade their surroundings, by disrupting cell-ECM interactions. They are also involved in the epithelial to mesenchymal transition ETM (see below). Because of the important role of MMP molecules in cancer progression, they have been targets of anti-cancer therapies and mouse models of MMPs have been developed [4][5]