Overview

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue homeostasis and favor tumor progression.

Cancer-associated fibroblasts (CAFs)

Fibroblasts produce collagen and are involved in tissue repair. During the natural process of wound healing, fibroblasts are transiently present for the initial healing process. Nevertheless, in cancer, the fibroblasts remain constitutively active so that they can remodel the extracellular matrix, induce angiogenesis, recruit inflammatory cells, and stimulate cancer cell proliferation.

Angiogenesis

Tumor growth is accompanied by active blood vessel growth at the tumor site due to the release of vascular endothelial growth factor or VEGF from the cancer cells and stromal cells. VEGF is an essential growth factor for angiogenesis during tumor progression. Therefore, therapies that can target the synthesis and activity of VEGF or the VEGF receptors in the tumor microenvironment have shown significant improvement in patient survival.

Adipose cells

Hypoxia in adipose or fat tissue is highly pro-inflammatory and promotes tumor formation and maintenance. Additionally, adipose cells secrete more than 50 different cytokines and chemokines that can increase the chances of tumor initiation. Excess adipocytes in the tumor microenvironment can lead to increased blood estrogen, chronic and low-grade inflammation resulting in cancer development.

ECM and tumor microenvironment

An extracellular matrix (ECM) is a dynamic and complex structure that supports tissues and cells. The ECM contains cytokines and growth factors secreted by the tumor and stromal cells. ECM components also include collagens, laminins, fibronectins, proteoglycans, and hyaluronans. The ECM helps tumors in several ways: First, ECM components facilitate angiogenesis by providing nourishment to the stalk cells, the building blocks of new blood vessels. Second, they act as chemoattractants to immune cells to initiate inflammation at tumor sites. Inflammation facilitates rapid cell division and angiogenesis. Third, altered collagen cross-links in the ECM allow tumor cells to escape immune surveillance and metastasize to new locations in the body.

Tumor management strategies must involve effective TME management. Targeting microenvironments can help create a hostile environment for tumor cells that may lead to effective therapy and hence, increase in patient survival.

Procedure

The tumor microenvironment comprises the tumor and the supporting tissue surrounding it, also known as the stroma. Tumor cells constantly interact with the stroma to form a permissive and supportive environment for their growth and metastasis.

The stroma consists of an extracellular matrix that surrounds the tumor and several cellular components.

The Extracellular Matrix, or ECM, is a complex network of macromolecules, including collagen and fibrin. Compared to normal tissues, the structure and composition of ECM in cancerous tissue are  modified to promote tumor progression.

For example, in breast cancer tissue, the increased expression of protease and oxidases degrade and linearize the dense network of cross-linked collagen fibers. This increases the stiffness of breast cancer tissue facilitating tumor cell migration.

The stroma also consists of Carcinoma-Associated Fibroblasts, or CAFs. They secrete several growth factors to aid cancer progression. For example, with the increase in tumor size, the demand for nutrients and oxygen increases. The innermost cancer cells in a solid tumor face acute oxygen limitation; a phenomenon called hypoxia.

CAFs secrete vascular endothelial growth factors that trigger the formation of new blood vessels around the growing tumor. This provides oxygen and nutrients to the rapidly dividing cells.

The immune cells, such as macrophages, lymphocytes, and natural killer cells, can detect the cancer cells and eliminate them. However, due to the increased genetic instability, cancer cells quickly acquire mutations to evade immune surveillance.

For example, tumor cells can induce immunosuppressive T-cells, which produce reactive oxygen species to inhibit the lymphocytes and prevent them from killing the tumor cells. The reactive oxygen species also increase the rate of mutations in tumor cells, facilitating rapid tumor progression.