Tumor microenvironment

The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells. The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells. The importance of a stromal microenvironment, especially “wound” or regenerating tissue, has been recognized since the late 1800s. The interplay between the tumor and its microenvironment was part of Stephen Paget's 1889 'seed and soil' theory, in which he postulated that metastases of a particular type of cancer ('the seed') often metastasizes to certain sites ('the soil') based on the similarity of the original and secondary tumor sites. Its role in blunting an immune attack awaited the discovery of adaptive cellular immunity. In 1960, Klein and colleagues found that in mice, primary methylcholanthrene-induced sarcomas exhibited an antitumor immune response mediated by lymph node cells to cancer cells derived from the primary tumor. This immune response did not however affect the primary tumor. The primary tumor instead established a microenvironment that is functionally analogous to that of certain normal tissues, such as the eye. Later, mice experiments by Halachmi and Witz showed that for the same cancer cell line, greater tumorigenicity was evident in vivo than the same strain inoculated in vitro. Unambiguous evidence for the inability in humans of a systemic immune response to eliminate immunogenic cancer cells was provided by Boon’s 1991 studies of antigens that elicit specific CD8+ T cell responses in melanoma patients. One such antigen was MAGE-A1. The coexistence of a progressing melanoma with melanoma-specific T cells implicitly does not involve immunoediting, but does not exclude the possibility of TME immune suppression. The discovery of melanoma-specific T cells in patients led to the strategy of adoptively transferring large numbers of in vitro-expanded tumor-infiltrating lymphocytes (TILs) which has proven that the immune system has the potential to control cancer. However, adoptive T cell therapy (ACT) with TILs has not had the dramatic success of ACT with virus-specific CD8+ T cells. The TME of solid cancers appears to be fundamentally different to that of the leukemias, in which clinical ACT trials with chimeric antigen receptor T cells have demonstrated efficacy. 80–90% of cancer are carcinomas, or cancers that form from epithelial tissue. This tissue is not vascularized, which prevents tumors from growing greater than 2mm in diameter without inducing new blood vessels. Angiogenesis is upregulated to feed the cancer cells, and as a result the vasculature formed differs from that of normal tissue. The enhanced permeability and retention effect (EPR) is the observation that the vasculature of tumors is often leaky and accumulates molecules in the blood stream to a greater extent than in normal tissue. This inflammation effect is not only seen in tumors, but in hypoxic areas of cardiac muscles following a myocardial infarction. This permeable vasculature is thought to have several causes, including insufficient pericytes and a malformed basement membrane. The tumor microenvironment is often hypoxic. As the tumor mass increases, the interior of the tumor becomes farther away from existing blood supply. While angiogenesis can reduce this effect, the partial pressure of oxygen is below 5 mm Hg (venous blood has a partial pressure of oxygen at 40 mm Hg) in more than 50% of locally advanced solid tumors. The hypoxic environment leads to genetic instability, which is associated with cancer progression, via downregulating DNA repair mechanisms such as nucleotide excision repair (NER) and mismatch repair (MMR) pathways. Hypoxia also causes the upregulation of hypoxia-inducible factor 1 alpha (HIF1-α), which induces angiogenesis and is associated with poorer prognosis and the activation of genes associated with metastasis, leading, for instance, to increased cell migration and also ECM remodeling.