The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resu...The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endothelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.展开更多
The reason why tumors generally have a modest or transient response to antiangiogenic therapy is not well understood. This poses a major challenge for sorafenib treatment of advanced hepatocellular carcinoma(HCC) wher...The reason why tumors generally have a modest or transient response to antiangiogenic therapy is not well understood. This poses a major challenge for sorafenib treatment of advanced hepatocellular carcinoma(HCC) where alternate therapies are lacking. We recently published a paper entitled "Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma" in the Journal of the National Cancer Institute, providing a potential explanation for this limited beneit. We found that in mice bearing HCCs that had acquired resistance to sorafenib, tumors had switched from using angiogenesis for growth to co-opting the liver vasculature by becoming more invasive. Accumulating evidence suggests that many human tumor types may use vessel co-option, which has profound implications for the use of anti-angiogenic agents for cancer treatment.展开更多
Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenome...Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenomenon of resistance was based on the fact that was targeting normal vessels rather than tumour cells prone to mutation and subject to drug induced selection.However,reality turned out to be more complex and since 1997,several mechanisms of resistance have been described to the point that the study of resistance to these drugs is now a very large field.Far from being exhaustive,this paper presents the main mechanisms discovered trough some examples.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant No.:81972811)the Key Research and Development Foundation of Shaanxi Province(Grant Nos.:2018SF-099,S2021SF-136,2021JM-273,and 2022JQ-848)+1 种基金the Fundamental Research Funds for the Central Universities(Grant No.:xzy012022094)the Provincial Science and Technology Rising Star(Grant No.:2021KJXX-03).
文摘The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endothelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.
文摘The reason why tumors generally have a modest or transient response to antiangiogenic therapy is not well understood. This poses a major challenge for sorafenib treatment of advanced hepatocellular carcinoma(HCC) where alternate therapies are lacking. We recently published a paper entitled "Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma" in the Journal of the National Cancer Institute, providing a potential explanation for this limited beneit. We found that in mice bearing HCCs that had acquired resistance to sorafenib, tumors had switched from using angiogenesis for growth to co-opting the liver vasculature by becoming more invasive. Accumulating evidence suggests that many human tumor types may use vessel co-option, which has profound implications for the use of anti-angiogenic agents for cancer treatment.
文摘Hailed as the cancer treatment to end all the resistance to treatment,anti-angiogenic therapy turned out to be not quite what was promised.The hope that this therapeutic approach would not have suffered by the phenomenon of resistance was based on the fact that was targeting normal vessels rather than tumour cells prone to mutation and subject to drug induced selection.However,reality turned out to be more complex and since 1997,several mechanisms of resistance have been described to the point that the study of resistance to these drugs is now a very large field.Far from being exhaustive,this paper presents the main mechanisms discovered trough some examples.
