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Cancerous cells have been the central focus for cancer research for decades as they allow tumors to autonomously grow and survive. However, malignant cells alone are far from the complete picture as tumors require support from a variety of surrounding cells. Malignant and non-malignant cells co-operate to promote tumor growth, resist cell death, induce angiogenesis, invade tissues and form metastases, all while avoiding the careful surveillance of the immune system1.
To develop a robust support system, malignant cells must recruit non-malignant cells from within the stromal tissue that would otherwise act to inhibit cancer development. Key stromal cells include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs) and vascular endothelial cells2. These cells interact with one another and the extracellular matrix (ECM) in a zone known as the tumor microenvironment (TME).
The process of recruiting and maintaining non-malignant cells involves complex inter- and intracellular signaling between malignant and stromal cells. Cancer cells aberrantly express cytokines, chemokines and growth factors, which stimulate supporting cells to secrete further bioactive molecules. These molecules can act in an autocrine, paracrine or juxtacrine manner to aid processes crucial for cancer development, such as tumor vascularization, metastasis and immune avoidance.
The interaction between the host and the cancer cell was first proposed by a 19th century English surgeon, Stephen Paget, with his “seed and soil” hypothesis. He argued that cancer cells (“the seeds”) selectively metastasize to neoplastic-promoting niches (“soil”).
After "seeding", cancer cells actively corrupt their microenvironment. This is achieved by cancer cells releasing paracrine growth factors, cytokines, and metabolites. These factors influence the generation of de novo vasculature for oxygen supply to the tumor, perturbation of signaling and metabolism in the surrounding stroma as well as protection of cancer cells from the immune surveillance. These changes to the microenvironment create a niche for the cancer cells that is permissive for their survival as well as growth. The TME is also clinically relevant as it can affect a cancer patient's prognosis and potentially confer drug-resistance, resulting in potential relapse and metastasis.
Similar to body organs, a growing tumor also requires a supply of blood to provide oxygen and blood-borne mitogens and remove toxic metabolites. Consequently, angiogenesis (the formation of new blood vessels) and vasculogenesis (the reorganization of existing blood vessels) are essential for tumor growth.
The TME plays an essential role in the formation and maintenance of tumor blood vessels. Multiple growth factors and cytokines co-operate to inhibit anti-angiogenic pathways and promote pro-angiogenic signaling. Key factors include vascular endothelial growth factors (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) and transforming growth factor-β (TGFβ).
Remodeling of the ECM, a protein network that holds stromal cells in place, is essential to accommodate the newly formed vessels. Fibroblasts and supporting immune cells release serine and cysteine proteases as well as metalloproteases that catalyze this restructuring. Also, these proteases can free additional mitogens that are sequestered in the ECM, further stimulating tumor growth1.
Tumor-associated blood vessels are essential for tumor growth and aid metastasis and immune avoidance.
Firstly, blood vessels that form in and around tumors are disordered and unstable, due to chronic activation of angiogenic pathways. They also display a ‘leaky’ morphology as a result of poor endothelial cell junctions and limited pericyte coverage3. This structure facilitates the accumulation of tumor-supporting immune cells and permits malignant cells to metastasize to different parts of the body.
Secondly, during normal immune surveillance, high endothelial venules (HEVs) provide an essential means of access of cytotoxic immune cells. However, tumor-associated vessels lack HEVs, resulting in the failure of cytotoxic immune cells (eg natural killer cells, cytotoxic T lymphocytes, etc) to accumulate within the TME to kill the cancer cells4.
Tumor-supporting cells permit the proliferation and escape of malignant cells into the bloodstream, allowing them to form metastases. For example, as well as promoting angiogenesis, VEGF signaling can loosen tight junctions between endothelial cells, enabling migration of cancer cells into the blood stream5.
Other growth factors also aid cancer cell survival, proliferation, invasion and metastasis. For example, EGF signaling has an important role both in cancer progression and the epithelial-to-mesenchymal transition (EMT), essential for metastasis. Along with over-production of EGF, aberrant EGF signaling can be triggered by over-expression of the membrane-bound receptor of EGF, EGFR, either by gene mutation or hypoxia6.
PDGF can act as a chemo-attractant for CAFs, which aid tumor development by creating the permissive stroma that is critical for tumor survival7. CAFs can secrete multiple factors that potentiate tumor progression, including HGF and TGFβ. HGF activates the c-Met receptor and stimulates proliferation and invasion8. TGFβ activates EMT pathways in cancer cells, making them more invasive and likely to metastasize, and can also inhibit cytotoxic immune cells from killing cancer cells9.
Under normal conditions, the immune system acts as our ally, clearing pathogens and preventing disease. However, cells of the immune system can be recruited by tumors to become our enemy from within.
Tumor growth also requires successful immune avoidance. How does the TME help malignant cells escape destruction by cells of the immune system?
Supporting immune cells secrete a variety of factors protecting cancer cells from immune detection. Thus, CAFs secrete CXCL12, a chemokine that coats cancer cells and prevents their destruction by cytotoxic T lymphocytes10. Supporting immune cells can also promote tumor cell survival by suppressing cell death pathways. For example, TAMs express integrin a4, which forms a complex with vascular cell adhesion molecule-1 (VCAM1) that suppresses apoptosis in metastatic breast cancer cells11.
6. Franovic, A., Gunaratnam L., Smith K., Robert I., Patten, D., and Lee, S. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. PNAS. 104,13092–13097 (2007).