Science: Tumor stem cell-driven positive feedback loops may be a new target for cancer treatment.

Tumor initiating cells , or TICs for short , are tumor stem cells , a class of tumor cells with self-renewing , cloning tumor generation capabilities and cloning long-term proliferation potential , forming a highly drug-resistant , asymmetrical division and initiation tumor cell population in tumors , closely related to tumor heterogeneity , and plays a key role in clinical phenomena such as recurrence , tumor sleep , tumor metastasis , and resistance after initial success in tumor release / chemotherapy.
the concept of TIC, the introduction of innovative treatment strategies for cancer, the aim is no longer simply to reduce the size of the tumor, but to eliminate the long-term growth of the tumor cell group - tumor stem cells.
However, the development rate of effective targeted TIC therapy is limited due to the lack of identification of TIC vulnerabilities.
, as are normal stem cells regulated by a special microenvironment or stem cell microenvironment, dry TICs are thought to be in such "niches".
this "niches" is a special microenvironment that regulates the fate of adult stem cells by providing cell-cell contact and secretion factors.
TIC is located in the "niches" itself is part of the tumor microenvironment, non-dry tumor cells are also members of it, in the process of tumor development to malignant state, the state of TIC in the primary tumor and its sub-malignant phenotype is controlled by various factors generated by the TIC-related tumor microenvironment, called "nic TICs".
therefore, an understanding of the mechanisms of interaction between TIC and TIC Nest will likely contribute to the development of effective cancer treatment.
normal stem cell "niches" consists of fibroblasts, immune cells, endothelial cells and peripheral cells of blood vessels or their progenitor cells, extracellular matrix (ECM) components, and cytokines and growth factor networks, and normal stem cells can coordinate the corresponding stem cell "niches" by sending short signals, followed by mutual signals, including TGF-beta, to maintain the stem cell's properties.
known solid tumors can recruit immune cells from the mesoplasmics, thus creating favorable conditions for their own growth and survival, in fact, the spatial distribution of tumor-soaked immune cells can be used to predict the survival rate and treatment response of patients.
However, how does the positioning and function of TIC-supportive immune cells be regulated by TIC when the space is adjacent? What does this have to do with the interaction between TIC and TIC niches? Recently, the Naoki Oshimori research team from Oregon Health and Science University in the United States published in Science entitled "Tumor-ageing cells cells cell an IL-33-TGF-beta niche signaling loop to promote progress cancerion" by focusing on cytokine environment and TGF Immune cells near TIC in the -beta response reveal the cell and molecular basis of the "TIC niches" interaction that promotes malignant tumor progression and resistance in squamous cell carcinoma (SCC) mouse models, thus providing a potential target for improving the efficiency of cancer treatment by making TIC unstable.
to study the "TIC niches" interactions in the early tumor microenvironments, the researchers first established a cancer-causing, H-RAS-driven SCC mouse model using intrauterine and epithelial-specific slow virus transduction.
histopathology showed different SCC regions - high-scoring and invasive, the lentiviral fluorescence reporting gene found tumor cells that responded to TGF-beta in invasive SCC (a slow-circulating TIC that produces invasive low differentiation children), and their production frequency was positively correlated with the distribution of TGF-beta ligands in adjacent substrates (Figure 1).
suggests that TICs for TGF-beta responses may have established specific interactions with cells adjacent to the interstitial (possibly "TIC niches") to maintain a titume-rich microenvironment, which may be achieved through specific signal molecules sent by TIC.
to test these assumptions and find possible molecules, the researchers purified TGF-beta-positive and negative tumor substrate cells using flow cell fluorescence sorting techniques (FACS) and compared their transcription group differences through RNA sequencing.
results found a series of NRF2 target genes involved in antioxidant response (NRF2 mediated antioxidant response is one of the characteristics of Tics of TGF-beta response), in which the IL-33 gene was significantly highly expressed in tumor cells with TGF-beta response, and the absence of TGF-beta receptors in tumor cells was significantly associated with the reduction of IL-33, indicating that TGF-beta signals were involved in SCCIL-33. further experiments
confirmed the high expression of IL-33 in tumor epithelial cells, which is also the main source of TIC cell groups for TGF-beta response.
, the researchers began looking for the reasons why tumor cells that triggered the TGF-beta response released IL-33.
under normal circumstances, IL-33 is stored in the nucleus of the cell and released into the extracellular space as an alarm cytokine in the event of cell damage.
study found that in the process of tumor gradualdevelopment to invasive SCC, IL-33 gradually appeared in the cytoplasm in the tumor base cells that were calledoprotein 5 positive (K5 plus).
at the same time, the cell plasma localization of The Il-33 of the Tumor Cells of the TGF-beta response is more common, suggesting that IL-33 may be released first from the TIC of the TGF-beta response in the adjacent interstitial. further mouse and human SCC tissue experiments and in vitro experiments
confirmed that the nRF2-mediated antioxidant reaction was activated in tic sycantis in the TGF-beta response, thereby promoting the extracellular release of IL-33.
further, the study found that il-33 tumors showed poor growth and good differentiation.
at the same time, compared with controlled tumors, the il-33 knockout of tumor epithelial cells in the TGF-beta-positive cells significantly reduced, but did not affect the TGF-beta-induced SMAD2 phosphorylation and cell inhibition reaction, indicating that the reduction of the TGF-beta signal caused by IL-33 knock-down is a non-cell autonomic effect, but due to the lack of GF-beta concentration of tumor microenvironment.
, after being given the tumor chemotherapy drug cisplatin, the results showed that the control tumor relapsed within 3 weeks, while the IL-33 knockout tumor did not grow.
show that tumor-derived IL-33 plays an important role in the production of TGF-beta response TIC, which promotes aggressive progression and drug resistance of SCC.
in-depth study found that high affinity IgE receptor Fc? RI alpha positive (Fc? RI alpha-plus cells, as tumor-related macrophages, can create a spatially different and TGF-beta-rich tumor microenvironment near TIC.
its specific mechanism is manifested in the FACT that TIC releases IL-33 that increases the adjacent mesoplasis in Fc? The density of RI alpha-tGF-beta-macrophage, mainly immature myelin cells can be recruited into tumor tissue through il-33 independent mechanisms, and IL-33 in the TIC microenvironment as a short-range hint, through the ST2-NF-B signaling pathway to induce immature myelin cells to differentiate into Fc? RI alpha plus macrophages activate side secretion of the TGF-beta signal and promote the aggressive progression of epithelial cells.
, a positive feedback model of "TIC niches" interaction is proposed in this paper.
tic's inherent NRF2-mediated antioxidant reaction triggers the release of IL-33 out of the cell in TGF-beta response TIC, thus enriching Fc in its vicinity? RI alpha-macrophages to induce TGF-beta-rich tumor microenvironments (Figure 2).
this self-reinforcing "TIC niches" signal loop has proven to be a key driver of invasive progression and resistance to human SCC, providing new targets for cancer treatment.
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