Deciphering the molecular mechanism of ICAM-1 as a novel therapeutic target in colorectal cancer

Abstract

Colorectal cancer (CRC) is the most common type of cancer and the leading cause of cancer mortality in both men and women. CRC can metastasize to the lungs and liver, and the 5-year survival rate at this time is less than 10%. Various anticancer drugs and targeted therapeutics currently used for the treatment of metastatic colorectal cancer are known to have insufficient therapeutic effect or to accompany complications. Therefore, research is needed to develop new targeted therapeutics. In this doctoral work, I present a novel discovery that intracellular adhesion molecule-1 (ICAM-1) is a potential target to enhance therapeutic effect on CRC. ICAM-1 is an important regulator of cell-cell interactions and recent studies have shown that it promotes malignancy in several carcinomas. However, the role of ICAM-1 in colorectal cancer is known to be controversial. Therefore, I analyzed multiple data sets of colorectal cancer patients to identify whether ICAM-1 is highly expressed in primary cancers and is associated with poor prognosis. As a results, expression of ICAM-1 correlated with malignancy and poor survival in colorectal cancer patients. Additionally, I conducted a study to define the mechanism by which ICAM-1 acts. ICAM-1 is phosphorylated by tyrosine-protein kinase Met (c-MET), and phosphorylated ICAM-1 can interact with SRC to increase SRC activity. Consequently, ICAM-1 may further accelerate SRC signaling, promoting the malignant potential of cancer. In addition, treatment with antibodies targeting ICAM-1 showed excellent therapeutic effects in reducing metastasis and angiogenesis. These findings suggest, for the first time, that ICAM-1 is an important adapter protein capable of mediating the c-MET-SRC signaling axis. Therefore, I suggest that ICAM-1 can be used as a novel therapeutic target and a metastatic marker for CRC.