Rectal cancer is one of the leading causes of cancer-related deaths worldwide, accounting for approximately 3.2% of all cancer-related deaths [1]. According to statistics, there are more than 700,000 new cases of rectal cancer worldwide every year, and more than 30% are late-stag

Rectal cancer is one of the leading causes of cancer-related deaths worldwide, accounting for approximately 3.2% of all cancer-related deaths[1]. According to statistics, there are more than 700,000 new cases of rectal cancer worldwide every year, and more than 30% are late-stage patients with poor prognosis.[2]. Neoadjuvant chemoradiotherapy combined with total mesorectal excision has become the standard treatment for locally advanced rectal cancer. However, different patients with locally advanced rectal cancer have different sensitivities to neoadjuvant treatment. Only 15-27% of patients can achieve pathological complete remission. response) , there are still 20-40% of patients whose tumors do not shrink significantly or even have no response at all to treatment [5, 6] . Therefore, analyzing the mechanism of heterogeneity in the response of patients with locally advanced rectal cancer to neoadjuvant chemoradiotherapy and accurately screening patients with locally advanced rectal cancer who respond to neoadjuvant therapy have become important clinical and scientific issues that need to be solved in the field of rectal cancer treatment!

Radiotherapy and chemotherapy can control the malignant proliferation of tumor cells by destroying their DNA. Double-strand breaks are considered to be the most important DNA damage during the cell killing process induced by radiotherapy and chemotherapy. The sensitivity of tumor cells to radiotherapy and chemotherapy depends to a large extent on their ability to repair DNA damage caused by radiotherapy and chemotherapy.[7]. DNA repair ability is affected by various metabolic factors in the microenvironment . Increasing evidence shows that, as a key player in host metabolism, intestinal microorganisms can influence the occurrence and development of colorectal cancer by inducing inflammation and immune responses. [8] , and its bacterial flora composition has also been reported to affect the sensitivity of tumor cells in response to treatment. [9, 10] . However, how these changes in gut microbiota affect the efficacy of neoadjuvant chemoradiotherapy in rectal cancer and the underlying regulatory mechanisms remain unclear.

On December 22, 2022, Peking University Cancer HospitalThe research group of Academician Zhan Qiminand the team of Professor Wang Weihu published a paper titled Cancer Cell titled Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal Articles by cancer and reveal the molecular basis of the impact of intestinal microorganisms on the efficacy of neoadjuvant radiotherapy and chemotherapy for locally advanced rectal cancer from the perspective of host-bacteria interaction.

The research team first enrolled 126 patients with locally advanced rectal cancer who received neoadjuvant chemoradiotherapy in the Department of Radiation Therapy, Peking University Cancer Hospital, and collected 353 stool specimens at different stages before, during, and after treatment and for efficacy evaluation (Figure 1) , through 16s rRNA amplicon sequencing found that the diversity of intestinal microorganisms in patients with rectal cancer was significantly reduced after neoadjuvant treatment, and the abundance of the bacterial flora that provides key energy sources for intestinal cells was found to be changed in the intestinal microbiota of patients with rectal cancer after radiotherapy and chemotherapy. This broadened people's understanding of the role of radiotherapy and chemotherapy in the treatment of rectal cancer from the perspective of intestinal microorganisms.

In order to further determine the relationship between intestinal microbial changes and patients' response to radiotherapy and chemotherapy, the research team divided patients into response and non-responder groups based on NCCN tumor regression grading guidelines and objective response. Through metatranscriptome analysis, they found that Bacteroides vulgaris (Bacteroides vulgatus) and nucleotide biosynthetic pathways were significantly enriched in the non-responsive group. The metabolome and abundance analysis of targeted metabolites of intestinal microorganisms also found that metabolites related to nucleotide biosynthesis were significantly increased in the non-responsive group. Multi-omics integration analysis found that Bacteroides vulgaris (B. vulgatus) played a dominant role in the significantly elevated nucleotide biosynthesis in the non-responder group.

In vitro cell experiments have confirmed that nucleoside supplementation can protect tumor cells from damage by 5-fluorouracil and ionizing radiation. By blocking the de novo biosynthesis of pyrimidine or purine , it can reduce the survival of tumor cells. The supplement of exogenous nucleosides can offset the inhibition of chemotherapy drugs on the de novo biosynthesis of pyrimidine or purine, thereby reducing double-stranded DNA damage in tumor cells and thereby surviving. Further use of inhibitors of nucleoside transporters to block the uptake of exogenous nucleoside can weaken the protective effect of nucleoside mixtures against 5-fluorouracil or ionizing radiation, and inhibit the repair of DNA double-strand damage after ionizing radiation, confirming that exogenous nucleoside supplementation can help tumor cells survive the blow of tumor treatment.

In vivo animal experiments have shown that nucleoside supplementation can effectively reduce DNA damage after ionizing radiation in subcutaneous transplanted tumors in mice. In order to better simulate the interaction between colorectal tumors and intestinal microorganisms in clinical patients, the research team further inoculated MC38 cells into the cecal wall of mice to establish an orthotopic colorectal cancer model. It was found that gavage feeding of B. vulgaris (B. vulgatus) significantly weakened the effect of 5-fluorouracil on tumor treatment, and this weakening could be reversed by inhibitors of nucleoside transporters. These results indicate that -mediated nucleotide biosynthesis of Bacteroides vulgaris (B. vulgatus) contributes to the resistance of orthotopic colorectal tumors to the damage caused by 5-fluorouracil treatment.

Gene set enrichment analysis of the transcript group in tumor tissues of rectal cancer patients after radiotherapy found that the expression of genes involved in DNA repair and nucleoside transport was increased in non-responsive tumors. Targeted metabolite analysis found that the levels of metabolites related to nucleoside biosynthesis were increased in the plasma and tumor tissues of non-responsive rectal cancer patients after radiotherapy and chemotherapy. Uric acid in serum is a metabolite of exogenous and endogenous purine breakdown, and its abundance fluctuates with changes in nucleotide biosynthetic activity. The research team further analyzed 2205 serum samples from 735 patients and found that compared with responders, there was no effect after radiotherapy and chemotherapy. Serum uric acid levels are elevated in patients with rectal cancer, and serum uric acid levels are significantly associated with poor prognosis in patients with locally advanced rectal cancer after neoadjuvant chemoradiotherapy, suggesting that serum uric acid levels are a potential marker for evaluating the prognosis of patients with rectal cancer following chemoradiotherapy.

In summary, This study found that Bacteroides vulgaris (B. Vulgatus) -mediated nucleotide synthesis can affect the efficacy of neoadjuvant treatment of locally advanced rectal cancer by promoting DNA repair of tumor cells, revealing the mechanism by which intestinal microorganisms affect the efficacy of neoadjuvant treatment of rectal cancer, and confirming the importance of studying the interaction between tumor cells and intestinal microorganisms during tumor treatment.

Peking University Cancer Hospital Teng Huajing , Wang Yan and Sui Xin is the co-first author of the paper, Academician Zhan Qimin and Professor Wang Weihu are the co-corresponding authors.

Figure 1 Research process and research summary

Original link:

https://doi.org/10.1016/j.ccell.2022.11.013