The research group of Prof. Xu Rui-hua from the Sun Yat-sen University Cancer Center, after several years of research, had a breakthrough in identifying biomarkers for colorectal cancer development, metastasis and chemotherapy responsiveness. The results of these researches have recently been published in the Journal of Hepatology, Clinical Cancer Research andCarcinogenesis.
According to CDC of Guangzhou, the incidence of colorectal cancer (CRC) in Guangzhou has increased by 50% in the past 10 years, and CRC has now become the second most common cancer with an incidence of 34/100,000. In other words, there are 7.5 people diagnosed with colorectal cancer in Guangzhou everyday.
Prof. Xu is a renowned expert in the diagnosis and treatment of gastrointestinal cancer. He has been focusing on the research of CRC for more than 20 years. Prof. Xu’s main interest is on the identification of biomarkers for CRC development, metastasis and chemotherapy responsiveness, so as to select out high-risk patients and guide personalized treatment.
Clinically, sporadic colorectal cancer is mainly evolved from adenoma. Normal colonic mucosa to adenoma developing into colorectal cancer is the classic pattern of this disease; this process generally taking more than ten years even decades to occur. However, not all adenoma will develop into malignant tumor; it is reported that about 10% of the adenoma will eventually become CRC.
How to screen out the high-risk adenoma patients and guide personalized therapy is of great importance. The group of Prof. Xu found out that Paxillin, an adaptor protein, is significantly overexpressed in tumor tissues compared with adenoma tissues, indicating that Paxillin might be involved in the development of CRC. Further study demonstrated that Paxillin is the down-stream target of miR-137, down-regulation of miR-137 resulting in overexpression of Paxillin, which leads to the development and progression of CRC. The study indicates that Paxillin might be a potential biomarker to predict those adenoma patients who are more likely to develop cancer, thus guiding treatment and follow-up strategy for the patients, and adding some information to the only diagnosis of CRC.
Metastasis is another important issue of CRC. Recent developments in the comprehensive treatment significantly increased the survival rate of CRC patients. However, patients with distant metastasis still have adverse prognosis. The liver is the most common site for distant metastasis, and liver metastasis is a common cause of cancer-related deaths in CRC patients. Clinically, approximately 25% of CRC patients present synchronous liver metastases at diagnosis, while other advanced CRC patients develop metachronous liver metastases within 3 years of treatment. Most CRC patients with liver metastases are not suited for surgery; as a result, the 5-year survival rate after liver metastasis diagnosis is no higher than 10%. In contrast, the 5-year survival rate for patients with early-stage CRC is more than 90%. Therefore, it is urgently necessary to unravel the underlying molecular mechanisms and genetic alterations that lead to CRC metastases.
Recently, Prof. Xu and his group found out that dysregulation of microRNAs (miRNAs) might play an important role in the development of CRC liver metastasis. miRNA microarray was performed to detect the expression profile in CRC tissues with or without liver metastasis, and a panel of 39 miRNAs were found to be differentially expressed between CRC with and without liver metastasis. Among these miRNAs, miR-214 was confirmed to be the critical miRNA that mediate CRC liver metastasis. Further investigation revealed that down-regulation of miR-214 leads to overexpression of its target gene: FGFR1, and resulted in CRC liver metastasis. It is worth noticing that small molecule inhibitors targeting FGFR1 are undergoing clinical trials in many tumors (excluding CRC), and this study indicates that FGFR1 inhibitor might also be used for treating CRC patients (especially those with liver metastasis) in the near future.
An important factor that affects the therapeutic effectiveness is drug resistance, which often leads to failure of treatment in patients. Therefore, it will be helpful to find some molecule that can be used to predict or even increase chemotherapy responsiveness. The group of Prof. Xu reported that a clock gene Bmal1 can inhibit cell proliferation, promote cell apoptosis as well as increase the responsiveness of CRC cells to Oxaliplatin both in vitro and in vivo mouse model. These results shed more light on the molecular mechanism of drug resistance of CRC, and targeting Bmal1 might become a new strategy to increase the chemotherapy responsiveness of CRC patients.
In conclusion, the findings of Prof. Xu’s group add much valuable information not only to the diagnosis, molecular mechanism of liver metastasis, but also the strategy to increase chemotherapy responsiveness, and these will greatly contribute to the diagnosis and treatment of CRC.
Links to the papers:
http://www.ncbi.nlm.nih.gov/pubmed/24616020
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