Resting tumor stem cells are the root cause of cancer recurrence and drug resistance

Resting tumor stem cells are the root cause of cancer recurrence and drug resistance.  Tumor recurrence and metastasis are directly related to resting tumor stem cells. Although traditional tumor treatment can kill tumor cells in a proliferating state, resting tumor stem cells may become resistant through mutation.

Telomere (Telomere) is a cap-like structure (TTAGGG repeat sequence) that exists at the end of eukaryotic chromosomes and maintains a stable genome. The telomere length of most somatic cells is not maintained by Telomerase as the cell divides. And keep shortening, and eventually go to aging. However, it is known that more than 90% of tumor cells can rely on telomerase to extend telomeres to achieve an immortalization state. However, the effect of simply inhibiting telomerase activity to treat tumors is not good.

Colorectal cancer (Colorectal Cancer, CRC) is the third most common malignant tumor, and its mortality rate also ranks third in the world. Although the early screening, targeted and immunotherapy of bowel cancer have become popular in recent years, according to the latest CA: A Cancer Journal for Clinicians
Colorectal Cancer Statistics, 2020 (colorectal cancer statistics report in 2020) shows that the survival rate of colorectal cancer treatment is still not optimistic and the incidence is younger, and more and more studies have shown that tumor metastasis and recurrence are the majority of colorectal cancers The leading cause of death in end-stage patients.

First-line treatments represented by 5-fluorouracil and oxaliplatin are mainly targeted at proliferating tumor cells. Although it can significantly improve the early treatment effect, patients often develop drug resistance and lead to recurrence and metastasis.

Further research found that Cancer Stem Cell (CSC) is the potential culprit for the recurrence of colorectal cancer patients after treatment. The remaining cancer stem cells can not only maintain their own stem cell characteristics, but also provide new supplements for the continued growth of tumors. This shows that cancer stem cells are the initiators of tumor recurrence and metastasis. Although the existence of cancer stem cells in a variety of tumors has become a consensus, why cancer stem cells develop drug resistance, what are the mechanisms of drug resistance, and the true characteristics of cancer stem cells have not been well analyzed for a long time. Tumor heterogeneity is closely related, and it is also related to the limitations of traditional tumor research as a mixed whole.

Recently, researchers from Nankai University, Southern Medical University, Tianjin Medical University, and Yale University collaborated to publish a research paper titled “Colorectal cancer stem cell states uncovered by simultaneoussingle-cell analysis of transcriptome and telomeres” in Advanced Science magazine. , Using integrated single cell technology to reveal the specific characteristics of colorectal cancer stem cells.

The research team used single-cell transcriptome integrated telomere length detection technology to find that colorectal cancer stem cells are in a resting state and have relatively short telomere length, and under certain conditions can be transformed into fast-growing tumor cells with extended telomeres These resting tumor stem cells may be the root cause of tumor recurrence and drug resistance.

Based on previous research, the research team established a set of analytical methods (scT&R-seq) that can simultaneously quantify telomere length and transcriptome (SMART-seq2) at the single-cell level, and then use this technology to analyze the primary generation of patients. Colorectal cancer was analyzed in depth.

First, the traditional and widely used cancer stem cell markers (CD44, CD133, LGR5) were used to enrich cancer stem cells. As a result, it was found that the “tumor stem cell” populations marked by these known markers have more complex heterogeneity. The proportion of truly strong stem cells is extremely rare.

Surprisingly, tumor stem cells have low proliferative activity, are in a resting state, and have relatively short telomere length. The simulation results show that cancer stem cells can be remodeled into tumor epithelial cells (Cancer Epithelial Cell, EPC), these tumor epithelial cells have high proliferation activity, and have longer telomeres, and telomerase and other related genes for telomere maintenance are activated. .

Subsequently, the 10×Genomics platform was used to conduct a larger-scale single-cell analysis of the entire tumor tissue and adjacent tissues. The 10×Genomics data further verified the analysis results of SMART-seq2. Not only that, by analyzing the copy number variation (CNV) in the 10×Genomics single-cell transcriptome, it is found that cancer stem cells have more CNVs compared to normal stem cells. These characteristic CNVs can well combine normal stem cells with Differentiate cancer stem cells.

Interestingly, the same analysis of tumor epithelial cells found that the CNV of tumor epithelial cells also has obvious specific characteristics, and these characteristic CNVs are highly consistent with tumor stem cells, further suggesting that the proliferating tumor epithelial cells are derived from resting. State of cancer stem cells. In addition, the researchers also found that the characteristic expression genes of tumor stem cells and tumor epithelial cells are closely related to the prognosis of colorectal cancer.

The results indicate that tumor recurrence and metastasis are directly related to resting tumor stem cells. Although traditional tumor treatment can kill tumor cells in a proliferating state very well, resting tumor stem cells may develop resistance through mutation. Medicinal properties.

Similarly, telomerase inhibitor drugs can only act on proliferating telomerase-positive tumor cells, but cannot target tumor stem cells with short telomeres and low telomerase activity. These findings will help provide a reference for further optimizing current treatment strategies to target cancer stem cells and alleviate tumor drug resistance, and achieve effective treatment and prevent colorectal cancer from recurring.

(source:internet, reference only)

Disclaimer of medicaltrend.org