The tumor microenvironment: an interplay of the tumor, stromal cells and immune system

The tumor microenvironment (TME) consists of various support cells subverted by the cancer cells to assist in the progression of the tumor. Learn more about the complex interplay of the tumor, stromal cells and immune cells within the TME. 

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​​​​Tumor microenvironment – an overview 

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.

​​​​"Seed and soil" hypothesis of tumor microenvironment

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.

    Role of the tumor microenvironment during vascularization

    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.

    Role of growth factors in the tumor microenvironment 

    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.

    ​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 vessels1.

    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.

    Discover more TME resources

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    References

    1. Hanahan, D., and Coussens, L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 21, 309–322 (2012).

    2. Junttila M.R., and de Sauvage F.J. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 501, 346–354. (2013).

    3. McDonald, D.M., and Baluk, P. Significance of blood vessel leakiness in cancer. Cancer Res. 62, 5381–5385 (2002).

    4. Fisher, D.T., et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J. Clin. Invest. 121, 3846–3859 (2011).

    5. Weis, S., Cui, J., Barnes, L., and Cheresh, D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol. 167, 223–229 (2004).

    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).

    7. Pietras, K., Pahler, J., Bergers, G., and Hanahan, D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 5:e19. (2008).

    8. Grugan, K.D., et al. Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion. PNAS. 107, 11026–11031 (2010).

    9. Yu, Y., et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br. J.Cancer. 110, 724–732 (2014).

    10. Feiga, C., et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. PNAS. 110, 20212–20217 (2013).

    11. Chen, Q., Zhang, X.H., and Massagué, J. Macrophage Binding to Receptor VCAM-1 Transmits Survival Signals in Breast Cancer Cells that Invade the Lungs. Cancer Cell. 20, 538–549 (2011).