Dissecting the role of laminin and Stat3 in colorectal cancer

© 2018 Dr. Yan QinColorectal cancer (CRC) represents the 3rd most common causes of cancer-related death in the world, with increasing number of cases diagnosed every year in Australia. CRC is known to be associated with chronic inflammation, which induces responses in the tumour microenvironment (TME) including remodelling of the extracellular matrix (ECM) and aberrant activation of the key signalling effector Stat3. ECM remodelling is a crucial cellular event during tumour invasion and an essential step towards metastatic progression and/or tumour recurrence metastatic sites. Laminins are among the key ECM proteins that have been shown to regulate tumour invasion, and this study examined whether this could involve a role for laminins in the regulation of cancer stem cells (CSCs). CSCs represent a rare tumour cell subpopulation with enhanced self-renewal properties and a demonstrated role in tumour initiation and progression and therapy resistance. Here, we characterized the role of laminin-521 (LN-521), one of the laminin isoforms with a known function in maintaining normal stem cells, in the regulation of colorectal CSCs in vitro. Our results show that LN-521 promotes CSC self-renewal and invasion abilities and activates downstream signalling including Stat3. We identify the integrin isoforms mediating this effect, and provide results to suggest that LN-521 may contribute to poor survival of CRC patients, supporting its potential use of LN-521 as a prognostic marker for CRC. The impact of aberrant activation of Stat3 on primary tumour initiation and growth is well-described, but the consequences of it on the behaviour of metastatic CRC remain poorly understood. We therefore investigated the functions of Stat3 in metastatic tumours and their TME. This was performed by silencing Stat3 within tumour cells and/or within mice recipients in an orthotopic mouse allograft model of liver metastasis, the most prevalent type of CRC metastasis in patients. Our data indicate that Stat3 knockdown correlates with prolonged survival, reduced metastatic size, and decreased expression of genes implicated in tumour progression, which supports Stat3 being a potential therapeutic target for treating metastatic CRC