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A small number of tumor cells with long-term tumor-causing capabilities, the tumor-initiating cell (tumor-initiating cell, TIC), play a key role in the development and treatment resistance of cancer.
however, the development of effective TIC targeted therapy is limited due to the lack of identification of TIC vulnerability.
just as normal stem cells are regulated by external cues from specific microenvironments (i.e. stem cell niches), TIC's stem cell-like state and its offspring's malignant phenotype are controlled by various factors from tic-related tumor microenvironments ,so-called TIC niches.
therefore, a mechanism to understand the interaction between TIC and TIC niches can accelerate the development of persistent cancer treatment drugs.
although TIC niches are thought to have evolved through two-way interaction with TIC, the mechanism of TIC-TIC niche interaction is not clear in tumor development.
known solid tumors recruit immune cells in the matrix to create favorable conditions for their growth and survival.
however, little is known about how TIC regulates the positioning and function of TIC-supported immune cells near their space.
mouse model squamous cell carcinoma (SCC), researchers at Oregon Health and Science University in the United States have previously found that conversion growth factor beta (TGF-beta) induces the emergence of a portion of drug-resistant TICs, resulting in leaching, differentiated offspring.
they observed that these TGF-beta reactive tumor cells were spatially associated with local TGF-beta expression in adjacent substrates.
therefore, the mechanism that causes the "TGF-beta-rich" tumor microenvironment may be the basis for tic-TIC niche interactions and could be used as a new target for destabilizing TIC.
Given that normal stem cells coordinate their niches by sending short-range signals, the researchers hypothesized that TIC might send specific signal molecules to neighboring substrates to induce TIC-supported niches. in a new study
, by focusing on cytokinemilieu and immune cells near TGF-beta reactive TIC, the researchers determined how TICs produce a spatially unique niche microenvironment, which is necessary for SCC's leaching progression and resistance.
related findings were published in the July 17, 2020 issue of The Journal of Science under the title "Tumor-based-based cells an IL-33-TGF-beta niche signaling loop to promote cancerprogression".
looking for potential side-secreting regulators in the nearby tumor microenvironment, they found that leukocyte interleukin-33 (IL-33) was the highest rise in TGF-beta reactive TICs.
Given that IL-33 is normally stored in the nucleus of cells, they found that it is released into extracellular space in nRF2-mediated antioxidant reactions, which is a sign of TGF-beta reactive TIC.
this IC-33 from TIC is necessary for SCC's leaching progression and resistance.
mechanism, IL-33 induces a partial accumulation of tumor-related macrophages of the IL-33 receptor ST2 and the high affinity IgE receptor (Fc-RI alpha) at a place close to TIC (i.e. within a radius of 50 m).
these previously unappreciated Fc-RI alpha-macrophages differentiate and alternating from bone marrow-derived cells, creating a niche microenvironment rich in TGF-beta through the IL-33-ST2-NF-B pathway, thus inducing the Secretion of TGF-beta signals to TIC, and further increasing the expression of IL-33.
blocking this pathway or removing Fc-RI alpha-macrophages can reduce the number of TGF-beta reactive TICs, reduce the rate of progression of invasive tumors and chemotherapy resistance tics for chemotherapy resistance treatment is considered to be the main culprit of cancer treatment failure.
by studying mouse models, the researchers revealed the cellular and molecular basis of TIC niches, in which TIC niches promote malignant progression and drug resistance in SCC.
they found an IL-33-TGF-beta niche signal cycle between TIC and FC-RI alpha-macrophage, which provides new insights into the mechanism sepulsied interaction of self-reinforcing TIC-TIC niches.
this interaction may be a potential target for destabilizing TIC to improve cancer treatment.
References: SachikoTaniet al. Tumor-starting cells cells an IL-33-TGF-beta niche signaling loop to promote cancer progression. Science, 2020, doi: 10.1126/science.aay1813. This article is from Bio Valley, for more information, please download Bio Valley APP (