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Tumor microenvironment – an overview
Cancer research has been focused on neoplastic cells for many decades, while its influence on surrounding cells and tissues they interact with (the "tumor microenvironment") has not had the same level of attention. Interactions between cancer cells and their stroma are vital for survival and progression of tumors, while also disrupting the surveillance of the immune system for developing tumors. Within a tumor, the stroma can consist of endothelial cells, fibroblasts, adipocytes, and immune cells, which are in close proximity to cancer cells.
"Seed and soil" hypothesis
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 a number of 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 of surrounding stroma; as well as masking of cancer cells from the immune system to prevent their destruction. These changes to the microenvironment create a niche for the cancer cell that is permissive for their survival as well as growth. The tumor microenvironment is also clinically relevant as it can affect a cancer patient's prognosis and potentially confer drug-resistance, resulting in potential relapse and metastasis.
Tumor microenvironment signaling
Tumor cells also contain CXCR4, the receptor for SDF-1, so stromal SDF-1 is able to directly stimulate tumor growth through a paracrine effect. Transforming growth factor-β (TGF-β) recruits EPC to the microenvironment and is involved in the transformation of fibroblasts to CAF, while platelet-derived growth factor (PDGF) is involved in recruiting fibroblasts and inducing their proliferation.
VEGF does not directly recruit fibroblasts, but indirectly supports microenvironmental changes via the creation of dysfunctional vascularization that allows plasma leakage, which attracts fibroblasts and other cells. Proteins secreted by the tumor modify the microenvironment by contributing growth factors and proteases that degrade the extracellular matrix and affect cell motility and adhesion.
Stromal cells secrete ECM proteins, cytokines, growth factors, proteases, and protease inhibitors. Tissue inhibitors of metalloproteinases (TIMP) are endogenous inhibitors of MMP and may function to balance the protease activity of MMP to shift the balance from a pro-angiogenic to an inhibitory environment.
The anti-tumor response
An anti-tumor immune response begins as a result of local tissue damage due to the expanding tumor and the release of “danger signals” from dead or dying tumor cells. A mature dendritic cell will then present acquired tumor antigens to T cells in the sentinel lymph node.
A pro-inflammatory cell-mediated immune response with NK cells, Th1 CD4+ T cells and CD8+ CTLs secreting IFN-Y releasing cytolytic granules are required for effective killing of tumor cells. However, many obstacles stand in the way of immune-mediated tumor cell killing including regulatory T cells, MDSC, tumor-derived exosomes, inhibitory molecules including MICA, CD47, EBAG9, CD274, SPI-6 and immunosuppressive cytokines such as IL-10 and TGF-β.