Abstract
Simple SummaryThe Wnt/β-catenin cell–cell signaling pathway is one of the most basic and highly conserved pathways for intercellular communications regulating key steps during development, differentiation, and cancer. In colorectal cancer (CRC), in particular, aberrant activation of the Wnt/β-catenin pathway is believed to be responsible for perpetuating the disease from the very early stages of cancer development. A large number of downstream target genes of β-catenin-T-cell factor (TCF), including oncogenes, were detected as regulators of CRC development. In this review, we will summarize studies mainly on one such target gene, the L1CAM (L1) cell adhesion receptor, that is selectively induced in invasive and metastatic CRC cells and in regenerating cells of the intestine following injury. We will describe studies on the genes activated when the levels of L1 are increased in CRC cells and their effectiveness in propagating CRC development. These downstream targets of L1-signaling can serve in diagnosis and may provide additional targets for CRC therapy.Cell adhesion to neighboring cells is a fundamental biological process in multicellular organisms that is required for tissue morphogenesis. A tight coordination between cell–cell adhesion, signaling, and gene expression is a characteristic feature of normal tissues. Changes, and often disruption of this coordination, are common during invasive and metastatic cancer development. The Wnt/β-catenin signaling pathway is an excellent model for studying the role of adhesion-mediated signaling in colorectal cancer (CRC) invasion and metastasis, because β-catenin has a dual role in the cell; it is a major adhesion linker of cadherin transmembrane receptors to the cytoskeleton and, in addition, it is also a key transducer of Wnt signaling to the nucleus, where it acts as a co-transcriptional activator of Wnt target genes. Hyperactivation of Wnt/β-catenin signaling is a common feature in the majority of CRC patients. We found that the neural cell adhesion receptor L1CAM (L1) is a target gene of β-catenin signaling and is induced in carcinoma cells of CRC patients, where it plays an important role in CRC metastasis. In this review, we will discuss studies on β-catenin target genes activated during CRC development (in particular, L1), the signaling pathways affected by L1, and the role of downstream target genes activated by L1 overexpression, especially those that are also part of the intestinal stem cell gene signature. As intestinal stem cells are highly regulated by Wnt signaling and are believed to also play major roles in CRC progression, unravelling the mechanisms underlying the regulation of these genes will shed light on both normal intestinal homeostasis and the development of invasive and metastatic CRC.
Highlights
Cell–cell adhesion is a basic biological process in multicellular organisms that determines cellular and tissue morphogenesis, and its disruption is a hallmark of cancer development
This study demonstrated that L1 is not expressed in the homeostatic intestinal epithelium, but its expression is required for colorectal cancer (CRC) organoid formation and metastasis initiation and growth
We found that overexpression of L1 in CRC cells induces the expression and nuclear accumulation of ASCL2, a decrease in E-cadherin levels, and increased levels of β-catenin in the nucleus, together with elevated β-catenin-T-cell factor (TCF) transactivation of Wnt/β-catenin target genes [52]
Summary
Cell–cell adhesion is a basic biological process in multicellular organisms that determines cellular and tissue morphogenesis, and its disruption is a hallmark of cancer development. Initial DNA microarray analyses of genes induced by activated β-catenin-TCF signaling in cancer cells identified two members of the L1 family of immunoglobulin-like cell adhesion receptors, NrCAM [21,22] and L1 [19] These findings were unexpected because both L1 and NrCAM were known to be present mostly in nerve cells, playing key roles during brain development by regulating a number of dynamic cellular processes including axonal growth, fasciculation, and pathfinding [23,24]. L1 is exclusively expressed at the invading edge of human CRC tissue (Figure 2) in the membrane of cells that display strong nuclear β-catenin staining, indicative of a highly active β-catenin-TCF transactivation [19] These results were recently confirmed and extended to show that, while L1 is not required for adenoma initiation, it plays multiple roles in cancer propagation, liver metastasis, and chemoresistance [33].
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