On January 25, 2018, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Sun Erxian Memorial and Su Shicheng team published a research paper entitled "CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness" in Cell Magazine, which was the first to use cell membrane proteins. CD10 and GPR77 affix an "identity tag" to a subset of fibroblasts associated with chemotherapy tolerance.
According to the latest data released by the National Cancer Registry, the annual incidence of breast cancer in women is about 249,000, which is the highest incidence of cancer among women in urban areas. The incidence and mortality rate have continued to rise in the past decade. Although the treatment of malignant tumors has been continuously updated in recent years, the mortality rate is still high. One of the important reasons is the existence of cancer drug resistance. Many cancer patients have a significant initial effect at the beginning of treatment, but as treatment time prolongs, cancer cells show strong resistance and ultimately lead to treatment failure. Therefore, to reverse the therapeutic tolerance of malignant tumors is of great significance to improve the efficacy of tumors, prolong the survival time of patients and improve the quality of life of patients. Therefore, the importance of finding the root cause of malignant tumor resistance can be seen. As we all know, tumor cells are like a "seed", and their growth is inseparable from fertile soil, the tumor microenvironment. Recent studies have shown that fibroblasts are the most abundant intrinsic interstitial cells in the tumor microenvironment and play a pivotal role in the treatment tolerance of malignant tumors.
Early studies have found that fibroblasts can promote tumor development, suggesting that it may be a good therapeutic target, but recent clinical trials have found that treatment of fibroblasts will accelerate the development of cancer patients. At the same time, previous studies have also suggested that tumor-associated fibroblasts are highly heterogeneous and lack effective surface markers, which leads to severe identification difficulties and hinders the study and targeting of different subpopulations of fibroblasts. Development of treatments.
"Rock" is a description of cancer in Chinese medicine. The ancestors have long recognized that "hard as stone" is an important clinical feature of malignant tumors. However, tumor cells are not actually hard, and the hard mass is due to the activation of collagen secretion by fibroblasts in the tumor microenvironment. Therefore, fibroblast activation is a common feature of malignant tumors.
Previous reports of the number of fibroblasts and patient prognosis are contradictory, suggesting that previous clinical models have difficulty studying the heterogeneity of tumor-associated fibroblasts. The study took the lead in the use of preoperative chemotherapy as a clinical model to study the heterogeneity of tumor microenvironment, effectively circumventing the impact of clinical treatments on the biological characteristics of tumors. The study found that the number of fibroblasts in untreated preoperative puncture specimens was not associated with future preoperative chemosensitivity. However, after preoperative chemotherapy, the number of fibroblasts in drug-resistant specimens was significantly higher than that in sensitive specimens. In vitro, the researchers co-cultured fibroblasts and tumor cells isolated from tumor specimens and found that fibroblasts isolated from drug-resistant specimens can induce co-cultured tumor cells to withstand chemotherapy-resistant drugs. Fibroblasts isolated from sensitive specimens cannot. Studies have further confirmed the existence of scientific hypotheses that different subpopulations of fibroblasts play different biological functions in malignant tumors. In addition, by comparing the differences in gene expression profiles of drug-resistant and sensitive specimen fibroblasts, the study identified a CD10+GPR77+ fibroblast subpopulation using two cell membrane proteins, CD10 and GPR77, and found the number of fibroblasts of this type. The prognosis of breast cancer and lung cancer patients is related to chemotherapy sensitivity. At the same time, the study suggests that the number of specific subgroups of fibroblasts detected by patient tumor specimens before treatment is expected to be an effective clinical indicator for predicting the prognosis and chemosensitivity of breast cancer and lung cancer patients, and can better guide clinical treatment programs. s Choice.
Since the specific subpopulation of fibroblasts has such a significant correlation with the chemosensitivity of breast cancer and lung cancer patients, is there a therapeutic value for targeted intervention of this group of cells? To maximize the patient's tumor microenvironment, the researchers used an animal model of patient-derived heterogeneous tumor (PDX). Human tumor specimens rich in CD10+GPR77+ fibroblasts were directly transplanted into mouse fat pads, and then treated with a blocking antibody of GPR77 membrane protein in combination with a chemotherapeutic drug. The experimental results show that antibody blocking therapy can significantly enhance the chemosensitivity of xenografts. This study provides a new target for the treatment of microenvironment reversal of tumor resistance, and has important research value.
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