The Tumor Microenvironment
Cancer research has improved understanding of potential treatment targets by expanding knowledge of the tumor microenvironment (TME).1 The TME includes cancerous cells, their supporting stroma, remodeled extracellular matrices, and recruited angiogenesis, all of which facilitate the proliferative and invasive growth of tumors.1 The various components within the TME provide a variety of targets for cancer therapeutics, and the improved understanding of the TME has allowed for advances that restrict the supportive environment that fosters tumor growth to improve patient outcomes.1
Vasculature and angiogenesis
The recruitment and formation of new blood vessels is a prime force supporting tumor health and proliferation, as oxygen and nutrients are necessary for cell survival.1 Vascular cells can provide growth factors, oxygen, and nutrients through the development of new blood supply to the tumor.1 Secretion of vascular endothelial growth factor (VEGF) can also contribute to blood-borne metastasis through impaired vascular integrity.1
The immune system
Immune cells within the TME have a variety of supporting roles. Infiltrating immune cells can supply mitogenic growth mediators, such as epidermal growth factor (EGF), transforming growth factor β (TGF-β), and tumor necrosis factor α (TNF-α), as well as various interleukins (ILs), chemokines, and histamines.1 Infiltrating immune cells can selectively cleave cell-adhesion molecules to disable growth suppression through expression of proteolytic enzymes, which modify the extracellular matrix, cell adhesion, and clustering.1 The presence and recruitment of regulatory T cells, tumor-associated macrophages (TAMs), and mast cells additionally allow for evasion of tumor suppression through the immune system.1 Regulatory T cells suppress response to self-antigens, and TAMs can bind cancerous cells through vascular cell adhesion molecule 1 (VCAM1), in turn activating receptor tyrosine kinase signaling and triggering suppression of apoptosis.1
The extracellular matrix
Cancer-associated fibroblasts (CAFs) are mesenchymal stem cells recruited and transformed into tissue-specific adipocytes or myofibroblasts.1 These cells produce distinctly altered and varied fibroblasts and secrete enzymes that can modify the extracellular matrix to facilitate tumor invasion into local tissue.1 CAFs can secrete additional growth factors, such as hepatocyte growth factor (HGF), EGF family of growth factors, and insulin-like growth factor 1 (IGF-1), to contribute to proliferation of the tumor and facilitate epithelial-to-mesenchymal transition to aid in metastasis.1 CAFs additionally allow tumors to evade the immune system through secretion of TGF-β.1 CAFs can be triggered by reactive oxygen species of cancerous cells to rely on aerobic glycolysis, allowing for additional energy supply to be readily available within the TME to increase tumor proliferation.1
Pathways to Cancer
Microsatellites and their contribution to cancer
Microsatellites are simple sequence repeats within the genome.2 They are generally located near the end of chromosomes but can be diffusely located in other coding and noncoding regions of the genome.2 Microsatellites are created through errors in DNA replication through strand slippage; in healthy tissue, microsatellites are corrected with the DNA repair system, mismatch repair (MMR).2
Microsatellite instability (MSI)
When MMR is absent or deficient, these microsatellites can accumulate and increase the possibility for genetic mutation and the development of tumors.2 Microsatellites can also alter noncoding regions that regulate the frequency of transcription and translation of various proteins, increasing the expression of key components that contribute to tumor development.2
MSI in tumor detection and treatment
Through next-generation sequencing, immunohistochemistry, and other methods, tissue can be identified by the frequency of MSI (ie, high MSI [MSI-H], low MSI [MSI-L], or microsatellite stable [MSS]).2 Recent advancements in MSI detection have identified programmed cell death ligand 1 (PD-L1) as an effective treatment of MSI-H tumors.2 MSI-H can be established in signature locations within specific cancer types, allowing for increased detection and improved targeted treatment strategies within cancer types.2
References: 1. Hanahan et al. Cancer Cell. 2012;21:309-322. 2. Li et al. Cancer Cell Int. 2020;20:16.
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