c-Met expression in primary tumors and their corresponding distant metastases

Abstract

Abstract. c-Met is a receptor tyrosine kinase that has been implicated in the pathogenesis and growth of a wide variety of human malignancies, including CRC, but its role in metastasis is largely unknown. We compared c-Met expression in primary human colorectal carcinomas and distant metastases from the same patients. Formalin-fixed paraffin-embedded tissue samples from 69 colorectal cancer patients were obtained. The protein expression of c-Met was evaluated immunohistochemically using a commercial antibody. The difference in expression between primary tumors and their corresponding distant metastases was analyzed using the Wilcoxon signedrank test. c-Met expression was statistically significantly lower in the distant metastases compared to their corresponding primary tumors (p<0.001), whereas no difference was found between lymph node metastases and their corresponding primary tumors (p=0.957). The degree of c-Met expression was not related to clinicopathological characteristics such as tumor grade and Dukes' stage at the time of primary tumor diagnosis, or to the location of the distant metastases. We demonstrated that c-Met expression is often reduced in distant metastases compared to their corresponding primary colorectal tumors. Additional studies of c-Met activation and signal transduction will increase our knowledge about the role of c-Met in colorectal cancer metastasis. IntroductionColorectal cancer (CRC) is the third leading cause of death in the western world with an overall 5-year survival of <60%. Succumbing to CRC is usually due to distant metastatic spread, with the liver being the most common site. Once distant metastases have been established, the chances of long-term survival are very low. Therefore, achieving an understanding of the molecular mechanisms contributing to the metastatic ability of a colorectal carcinoma is critical to the development of effective treatments.c-Met is a receptor tyrosine kinase that has been implicated in the pathogenesis and growth of a wide variety of human malignancies (1-3), including CRC (4-6). c-Met expression in colonic cells increases during the progression towards malignancy (7), and a higher c-Met expression has been observed in colorectal tumors compared with corresponding normal colon mucosa (8).The heterodimeric c-Met protein (9) is activated by hepatocyte growth factor (HGF), also known as scatter factor (SF) (9). The binding of HGF/SF to c-Met is known to promote motility, morphogenesis and mitogenesis in epithelial cell lines of various origins (10,11), causing colon cancer cells to form crypt-like structures (10) and inducing angiogenesis in endothelial cells (5).The c-Met signaling pathway is believed to stimulate tumor invasion and metastasis. The Madkin-Darby canine kidney (MDCK) cell line responds to HGF/SF by colony dispersal and epithelial-to-mesenchymal transition (EMT), increasing cell motility and the invasion of collagen matrices (12). c-Met stimulation by HGF/SF from stromal cells has been suggested to facilitate local invasion of epith...

Clinical impact of c‐MET expression and genetic mutational status in colorectal cancer patients after liver resection

“…Two studies showed that c-MET protein expression tended to be decreased in distant metastases compared to their corresponding primary tumors. ( 5 , 17 ) In contrast, Voutsina et al . ( 18 ) observed that c-MET expression tended to be increased in distant metastases compared to their corresponding primary tumors.…”

“…The frequency of expression of c-MET protein in CRC as detected by immunohistochemistry (IHC) has been reported to be between 59.4% and 81.1%; it is associated with advanced tumor stages and poor clinical outcomes. ( 5 )– ( 8 ) Similar to c-MET protein expression, c-MET gene amplification is linked to disease metastases. ( 9 , 10 ) The HGF/c-MET pathway is also well-known to be associated with liver regeneration and the development of normal organs, such as the placenta, muscle and the central nervous system.…”

“…Despite increasing evidence for a role of c-MET in CRC metastases, few studies have, to our knowledge, compared c-MET expression in primary CRC and distant metastases, and they have obtained conflicting results. ( 5 , 12 ) Furthermore, the significance of performing genomic testing for somatic mutations in KRAS , BRAF and PIK3CA is recognized in molecular target therapy,( 13 )– ( 16 ) but material from metastatic tumors is not always included in the testing. Therefore, it is important to investigate the concordance of results from primary tumors and paired liver metastases.…”

HER3 expression in primary colorectal cancer including corresponding metastases in lymph node and liver

“…This may be due to the relatively small sample size or to actual lack of biological difference. In a study by Ljuslinder et al, 67% of primary CRC tumours (n ϭ 64) showed high HER3 expression and there was a correlation with expression of HER3 in corresponding lymph node metastases, both membrane and cytoplasmic staining were considered [21]. In a study by Wei et al including 49 patients, they reported a HER3 expression in 16% of the primary CRC and 18% in corresponding lymph node metastases.…”

“…Cytoplasmic or background staining was not graded. The lower limit of positive expression of HER3 was set at 10% stained CRC cells according to literature [10,20,21]. The entire slide of the tumour or metastasis was evaluated.…”