L1 cell adhesion molecules as regulators of tumor cell invasiveness. Cell Adh Migr

Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA.
Cell adhesion & migration (Impact Factor: 4.51). 08/2009; 3(3):275-7. DOI: 10.4161/cam.3.3.8689
Source: PubMed


Fast growing malignant cancers represent a major therapeutic challenge. Basic cancer research has concentrated efforts to determine the mechanisms underlying cancer initiation and progression and reveal candidate targets for future therapeutic treatment of cancer patients. With known roles in fundamental processes required for proper development and function of the nervous system, L1-CAMs have been recently identified as key players in cancer biology. In particular L1 has been implicated in cancer invasiveness and metastasis, and has been pursued as a powerful prognostic factor, indicating poor outcome for patients. Interestingly, L1 has been shown to be important for the survival of cancer stem cells, which are thought to be the source of cancer recurrence. The newly recognized roles for L1CAMs in cancer prompt a search for alternative therapeutic approaches. Despite the promising advances in cancer basic research, a better understanding of the molecular mechanisms dictating L1-mediated signaling is needed for the development of effective therapeutic treatment for cancer patients.

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    • "This is in line with previous studies that highlighted the role of L1cam in progression and metastasis of a variety of tumor types, such as uterine and ovarian carcinoma, human malignant melanoma, glioma and colorectal cancer [31-36]. It has been reported that L1cam could bind to a variety of integrins, form a protein-protein complex and activate several signaling pathways to promote cell adhesion and motility [37]; these L1cam/integrin-mediated signaling transduction may also integrate with growth factor signaling networks to stimulate cellular motility [37]. In addition, L1cam enables endocytosis of integrins by tumor cells, thus reducing cell adhesion to the extracellular matrix and promoting cell migration [38]. "
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    ABSTRACT: Previous reports have demonstrated that L1cam is aberrantly expressed in various tumors. The potential role of L1cam in the progression and metastasis of gastric cancer is still not clear and needs exploring. Expression of L1cam was evaluated in gastric cancer tissues and cell lines by immunohistochemistry and Western blot. The relationship between L1cam expression and clinicopathological characteristics was analyzed. The effects of L1cam on cell proliferation, migration and invasion were investigated in gastric cancer cell lines both in vitro and in vivo. The impact of L1cam on PI3K/Akt pathway was also evaluated. L1cam was overexpressed in gastric cancer tissues and cell lines. L1cam expression was correlated with aggressive tumor phenotype and poor overall survival in gastric cancer patients. Ectopic expression of L1cam in gastric cell lines significantly promoted cell proliferation, migration and invasion whereas knockdown of L1cam inhibited cell proliferation, migration and invasion in vitro as well as tumorigenesis and metastasis in vivo. The low level of phosphorylated Akt in HGC27 cells was up-regulated after ectopic expression of L1cam, whereas the high level of phosphorylated Akt in SGC7901 cells was suppressed by knockdown of L1cam. Moreover, the migration and invasion promoted by L1cam overexpression in gastric cancer cells could be abolished by either application of LY294002 (a phosphoinositide-3-kinase inhibitor) or knockdown of endogenous Akt by small interfering RNA. Our study demonstrated that L1cam, overexpressed in gastric cancer and associated with poor prognosis, plays an important role in the progression and metastasis of gastric cancer.
    Full-text · Article · Jun 2013 · Journal of Hematology & Oncology
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    • "Besides its functions in the nervous system, L1 plays important roles in tumor progression and metastatis. L1 is expressed in a broad set of tumors comprising not only gastrointestinal stromal tumor, melanoma, neuroblastoma, Schwannoma, paraganglioma, pheochromocytoma of neuroepithelial and neural crest origin [16], but also in tumors of non-neural origin, such as granular cell tumor, chondrosarcoma and Kaposi sarcoma, capillary hemangioma, lymphoblastoma, and cancers of the esophagus, colon, and ovary [17], [18]. Because of its pivotal importance in repair of the nervous system and in the metastatic behavior of tumors, we sought to screen for antibodies that, by reacting with different domains of the human L1 molecule, would, on the one hand, trigger its beneficial functions and, on the other hand, inhibit the detrimental functions of the molecule. "
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    ABSTRACT: The neural cell adhesion molecule L1 plays important roles in neuronal migration and survival, neuritogenesis and synaptogenesis. L1 has also been found in tumors of different origins, with levels of L1 expression correlating positively with the metastatic potential of tumors. To select antibodies targeting the varied functions of L1, we screened the Tomlinson library of recombinant human antibody fragments to identify antibodies binding to recombinant human L1 protein comprising the entire extracellular domain of human L1. We obtained four L1 binding single-chain variable fragment antibodies (scFvs), named I4, I6, I13, and I27 and showed by enzyme-linked immunosorbent assay (ELISA) that scFvs I4 and I6 have high affinity to the immunoglobulin-like (Ig) domains 1-4 of L1, while scFvs I13 and I27 bind strongly to the fibronectin type III homologous (Fn) domains 1-3 of L1. Application of scFvs I4 and I6 to human SK-N-SH neuroblastoma cells reduced proliferation and transmigration of these cells. Treatment of SK-N-SH cells with scFvs I13 and I27 enhanced cell proliferation and migration, neurite outgrowth, and protected against the toxic effects of H(2)O(2) by increasing the ratio of Bcl-2/Bax. In addition, scFvs I4 and I6 inhibited and scFvs I13 and I27 promoted phosphorylation of src and Erk. Our findings indicate that scFvs reacting with the immunoglobulin-like domains 1-4 inhibit L1 functions, whereas scFvs interacting with the fibronectin type III domains 1-3 trigger L1 functions of cultured neuroblastoma cells.
    Full-text · Article · Dec 2012 · PLoS ONE
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    • "Given the high prevalence of mammary carcinoma, this corresponds to a large number of patients. The mechanisms by which L1 promotes tumour progression appear to be diverse (Siesser and Maness 2009; Schäfer and Altevogt 2010). For instance, L1 was shown to increase cell proliferation (Gavert et al. 2005) while several studies demonstrated ectodomain shedding of L1-CAM to promote cell migration (Mechtersheimer et al. 2001; Maretzky et al. 2005; Yang et al. 2009). "
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    ABSTRACT: Purpose: Expression of the adhesion molecule L1-CAM (L1) has been shown to correlate with early recurrence in breast cancer. Here, we investigated whether L1-CAM expression of breast cancer cells might influence adherence to human pulmonary microvascular endothelial cells (HPMEC) and thus promote metastasis. Methods: MDA-MB231-Fra2 breast cancer cells that express high levels of L1-CAM (L1(high) cells) were stably transfected to generate clones with strong L1-CAM downregulation. Adhesion to activated HPMEC was studied in dynamic cell flow and static assays. Potential binding partners on endothelial cells were identified by blocking experiments and adhesion assays after coating of the flow channels with recombinant proteins. Results: Adhesion of L1(high) cells to activated HPMEC was significantly higher compared to L1l(ow) clones under flow conditions. Blocking experiments and adhesion assays with recombinant proteins identified activated leucocyte cell adhesion molecule (ALCAM) or L1 itself, but not ICAM-1, as potential binding partners on endothelial cells. E-selectin blocking antibodies strongly diminished the adherence of breast cancer cells irrespective of their L1-CAM expression. Conclusions: Our experiments indicate that L1-CAM expression on breast cancer cells can promote adherence to activated endothelial cells by binding to endothelial L1-CAM or ALCAM. This mechanism might lead to increased metastasis and a poor prognosis in L1-CAM-positive carcinomas in vivo. Therefore, L1-CAM might be a suitable therapeutic target in breast cancers with a high L1-CAM expression.
    Full-text · Article · Sep 2012 · Journal of Cancer Research and Clinical Oncology
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