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It is easy to think of tumors as simply masses of malignant cells. But far from autonomous and self-sufficient structures, tumors require the support of surrounding non-malignant cells in order to survive and proliferate. This heterogeneous mix of malignant and non-malignant cells co-operates to promote tumor growth, resist cell death, induce angiogenesis, invade tissues and form metastases, all while avoiding the careful surveillance of the immune system (Hanahan and Coussens, 2012).
To develop a robust support system, malignant cells must recruit non-malignant cells from within the stromal tissue, the cellular milieu in which a tumor develops, that would otherwise act to inhibit cancer development. Key stromal cells include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs) and vascular endothelial cells (Junttila and de Sauvage, 2013). The zone in which these cells interact with one another and the extracellular matrix (ECM) is known as the tumor microenvironment (TME).
The process of recruiting and maintaining a legion of 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 that can act in an autocrine, paracrine or juxtacrine manner to aid processes crucial for cancer development, such as tumor vascularization, metastasis and immune avoidance.
Roles of the tumor microenvironment during vascularization
Just as organs within the body require constant blood supply to function normally, 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 act in concert 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. What’s more, these proteases can free additional mitogens that are sequestered in the ECM, further stimulating tumor growth (Hanahan and Coussens, 2012).
The physiological nature of tumor-associated blood vessels means that as well as being essential for tumor growth, they also 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 coverage (McDonald and Baluk, 2002). 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 (e.g., natural killer cells, cytotoxic T lymphocytes etc.) to accumulate within the TME to kill the cancer cells (Fisher et al., 2011).
Growth factors from the TME support tumor growth and metastasis
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 stream (Weis et al., 2004).
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) that is 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 hypoxia (Franovic et al., 2007).
PDGF can act as a chemo-attractant for CAFs, which aid tumor development by creating the permissive stroma that is critical for tumor survival (Pietras et al., 2008). CAFs can secrete multiple factors that potentiate tumor progression, including HGF (which activates the c-Met receptor and stimulates proliferation and invasion) and TGFβ (which activates EMT pathways in cancer cells, making them more invasive and likely to metastasize; Grugan et al., 2010, Yu et al., 2014). TGFβ can also inhibit cytotoxic immune cells from killing cancer cells.
Contribution of immune cells to the tumor microenvironment
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.
Cancerous lesions contain a wide diversity of lymphoid and myeloid lymphocytes. Instead of inducing cell death, these hijacked tumor-associated immune cells promote cancer progression by secreting growth signals and proteases, which stimulate cancer cells growth and the formation of tumor blood vessels. Important factors include: interleukins (ILs), chemokines, tumor necrosis factor-α (TNFα), VEGF, EGF, FGF, PDGF and TGFβ. The persistent expression of these factors by tumor-supporting immune cells stimulates cancer cell growth and the formation of tumor blood vessels (Hanahan and Coussens, 2012).
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 that protect cancer cells from immune detection. One example is the secretion of CXCL12 by CAFs. CXCL12 is a chemokine that coats cancer cells and prevents their destruction by cytotoxic T lymphocytes (Feiga et al., 2013). Supporting immune cells can also promote tumor cell survival by suppressing cell death pathways. An example of this mechanism is the expression of integrin a4 by TAMs, which forms a complex with vascular cell adhesion molecule-1 (VCAM1) that suppresses apoptosis in metastatic breast cancer cells (Chen et al., 2011).
The tumor microenvironment (TME) is made up of a variety of support cells, which are subverted by the cancer cells to assist progression of the tumor. The TME plays a key role in cancer cell proliferation, immune cell avoidance and survival, as well as metastasis. In the coming years, it will be exciting to see how researchers dissect the complex interplay of the tumor, stromal cells and immune cells within the TME, and how those discoveries translate into therapeutics that target cancer-supporting aspects of the tumor microenvironment.