Mini-reviewL1 cell adhesion molecule (L1CAM) in invasive tumors
Introduction
Identification of biological markers associated with advanced stages of tumor progression is necessary for early diagnosis of patients with aggressive tumors and poor prognosis, and to develop new therapeutic strategies that will provide patients with appropriate treatment. Progression from the primary tumor to metastasis formation is associated with changes in different cellular properties. These include the disruption of cell–cell and cell–extracellular matrix (ECM) adhesions, and the associated alterations in the expression of cell adhesion molecules that together constitute key steps during the progression along the different stages of tumor development. Therefore, the identification and inhibition of the function of such molecules could be useful for blocking cancer progression. Members of all major cell adhesion molecule families (integrins, cadherins, immunoglobulin-like CAMs and selectins) are often aberrantly regulated in human cancer, contributing to the progression of cancer development. One such molecule, L1CAM, was reported in recent years to be involved in the formation of a variety of human cancers. L1CAM is a cell adhesion molecule of the immunoglobulin superfamily of cell adhesion molecules (IgCAM), initially identified in the nervous system [1]. It has an extracellular region composed of six immunoglobulin-like domains and five fibronectin type III repeats, a single transmembrane sequence and a highly conserved cytoplasmic domain [2].
Originally, L1CAM was shown to play a key role in development of the nervous system, regulating cell–cell interactions, neuronal migration, the outgrowth of neurites on Schwann cells, neurite fasciculation and myelination [3]. These important functions of L1CAM in the nervous system were further supported by the observation that different mutations in the L1CAM gene are responsible for various neurological disorders [4], and by later studies on the phenotype of L1CAM knockout [5], [6], [7], [8] and transgenic mice [9], [10]. Mutations in the human L1CAM were suggested to be responsible for the CRASH syndrome (abbreviation of corpus callosum hypoplasia, mental retardation, adducted thumbs, spastic paraplegia and hydrocephalus) [11]. In addition, recent studies have demonstrated aberrant expression of L1CAM in several different types of human cancer (described in detail below). The presence of L1CAM in cancer tissue and cultured cells was correlated with poor prognosis and more advanced stages of the disease. Moreover, L1CAM was recently identified as a target gene of the Wnt/β-catenin signaling pathway [12] that is hyperactivated during the development of colorectal cancer in the majority of the cases, and also (to varying extents) in almost all types of human cancer [13].
Section snippets
Mutations in the Wnt pathway are involved in colon cancer progression
The Wnt signaling pathway is essential in maintaining the homeostasis of the normal colon epithelium regulating the proliferation, differentiation and positioning of epithelial cells along the crypt-villus axis. The bottom of the crypt, where the stem cell compartment is localized, is characterized by nuclear localization of β-catenin, while along the crypt most epithelial cells express β-catenin in the cell membrane in adherens junctions, where β-catenin is linking the E-cadherin adhesion
L1CAM is a target gene of β-catenin-TCF signaling
Several target genes of β-catenin signaling are among the primary genes induced during tumor initiation. Among the first genes identified as targets of β-catenin-TCF signaling are genes contributing to the onset of oncogenesis such as Cyclin D1[25], [26] and c-Myc[27], known for their involvement in promoting cell proliferation by affecting cell cycle progression. Although mutations in components of the Wnt pathway occur already at the initiation of tumor formation, β-catenin accumulation in
L1CAM is involved in advanced stages of colon cancer progression and metastasis
The transfection of L1CAM into LS174T human colon cancer cells that do not express endogenous L1CAM, resulted in higher growth rate, increased cell motility, cell transformation and enhanced tumorigenic capacities [12]. In addition, L1CAM expression in LS174T cells conferred the capacity to form metastases in the liver upon injection of these cells into the spleen of nude mice [35]. Moreover, a DNA microarray analysis of RNA levels from LS174T–L1CAM cells revealed that about 40% of the genes
L1CAM involvement in various other human cancers
A role for L1CAM in the cancerous process was not only detected in colon cancer, but also in other types of cancer. The possible involvement of L1CAM in cancer was first demonstrated by investigating the presence of L1CAM in B16 melanoma cells. L1CAM expression was observed in both low metastatic B16-F1 and in high metastatic B16-F10 cells [47]. However, a further study demonstrated L1CAM expression only in metastatic, but not in non-metastatic melanoma cells [48]. In melanoma tumor tissue,
L1CAM affects various signaling pathways
L1CAM plays a role in cancer by affecting different signaling pathways that conceivably contribute to tumor progression. As a transmembrane molecule, both the extracellular and intracellular domains of L1CAM are apparently involved in cancer promotion (see above [12], [56] and Fig. 2). Recent studies demonstrated that the cytoplasmic domain of L1CAM plays an important role in carcinogenesis by its activation of the extracellular signal-regulated kinase (Erk) [68], [69], [70], [71], [72].
L1CAM as a target molecule for cancer therapeutics
While L1CAM is expressed in a wide variety of human cancers, its presence in normal tissue was observed only in the nervous system and in a small number of other tissues including leukocytes [81], epithelial cells of the urogenital tract [82] and epithelial cells of mouse intestinal crypts (but not in the human intestine) [83]. This feature of L1CAM expression, mostly in cancerous tissue and rarely in normal tissue, in addition to its cell surface localization, makes L1CAM a possible useful
Conclusions
L1CAM was originally found to be expressed in the nervous system. In recent years, the expression of L1CAM was also detected in a growing number of different cancers, including glioma [54], [55], melanoma [49], [50], [52], ovarian carcinoma [59], [60], [61], colon cancer [12], [45], [46], breast cancer [56], [57], and other less common types of cancer. Alterations in the expression of cell adhesion molecules play a key role in tumor progression and contribute to metastasis formation in distant
Conflicts of Interest
None declared.
Acknowledgements
The studies from the authors’ laboratory were supported by grants from the Israel Science Foundation, the Yad Abraham Center for Cancer Diagnosis and Therapy, The Israel Cancer Research Fund (ICRF), and by a Research Grant from Dr. and Mrs. Arnold and Esther Leibowitz.
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