CD151 drives cancer progression depending on integrin α3β1 through EGFR signaling in non-small cell lung cancer (original) (raw)
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Cancers, 2021
As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), and the Wnt/β-catenin pathway, as well as the dynamics of exosome and cellular metabolism. Finally, we discuss the implications of the highly plastic nature and epigenetic susceptibility of CD151 expression, function, and signal...
Prognostic significance of CD151 overexpression in non-small cell lung cancer
Lung Cancer, 2013
The overexpression of tetraspanin CD151-a transmembrane protein that promotes tumor invasion and metastasis-is associated with poor prognosis in various cancers. However, its clinical significance in non-small cell lung cancers (NSCLCs) has not been fully elucidated. We investigated CD151 expression status by immunohistochemical analysis in paraffin-embedded specimens obtained from 380 patients with surgically resected NSCLCs (245 squamous cell carcinomas [SCCs] and 135 adenocarcinomas [ADCs]) between 1994 and 2001. High CD151 expression was detected in 28.7% NSCLCs (20.8% of SCCs and 42.9% of ADCs) and was significantly associated with male gender, smokers, and ADCs. Moreover, elevated CD151 levels were correlated with reduced overall (OS) and disease-free survival (DFS), and were an independent negative prognostic factor for OS in NSCLC. According to histological type, high CD151 expression was an independent prognostic factor for lower OS in ADC, although not in each subtype, and the elevated CD151 expression levels were more common in solid-predominant tumors (48.3%). In contrast, there was no prognostic correlation in SCC. High CD151 expression appeared to correlate with aggressive behavior in NSCLC, suggesting that it may be a useful prognostic marker for lung ADC patients and a potential molecular target for NSCLC treatment.
Cancer Research, 2008
CD151, a master regulator of laminin-binding integrins (α6β4, α6β1, and α3β1), assembles these integrins into complexes called tetraspanin-enriched microdomains. CD151 protein expression is elevated in 31% of human breast cancers and is even more elevated in high-grade (40%) and estrogen receptor–negative (45%) subtypes. The latter includes triple-negative (estrogen receptor, progesterone receptor, and HER2 negative) basal-like tumors. CD151 ablation markedly reduced basal-like mammary cell migration, invasion, spreading, and signaling (through FAK, Rac1, and lck) while disrupting epidermal growth factor receptor (EGFR)-α6 integrin collaboration. Underlying these defects, CD151 ablation redistributed α6β4 integrins subcellularly and severed molecular links between integrins and tetraspanin-enriched microdomains. In a prototypical basal-like mammary tumor line, CD151 ablation notably delayed tumor progression in ectopic and orthotopic xenograft models. These results (a) establish tha...
Cancer Research, 2008
CD151, a master regulator of laminin-binding integrins (A 6 B 4 , A 6 B 1 , and A 3 B 1 ), assembles these integrins into complexes called tetraspanin-enriched microdomains. CD151 protein expression is elevated in 31% of human breast cancers and is even more elevated in high-grade (40%) and estrogen receptor-negative (45%) subtypes. The latter includes triplenegative (estrogen receptor, progesterone receptor, and HER2 negative) basal-like tumors. CD151 ablation markedly reduced basal-like mammary cell migration, invasion, spreading, and signaling (through FAK, Rac1, and lck) while disrupting epidermal growth factor receptor (EGFR)-A 6 integrin collaboration. Underlying these defects, CD151 ablation redistributed A 6 B 4 integrins subcellularly and severed molecular links between integrins and tetraspanin-enriched microdomains. In a prototypical basal-like mammary tumor line, CD151 ablation notably delayed tumor progression in ectopic and orthotopic xenograft models. These results (a) establish that CD151-A 6 integrin complexes play a functional role in basallike mammary tumor progression; (b) emphasize that A 6 integrins function via CD151 linkage in the context of tetraspanin-enriched microdomains; and (c) point to potential relevance of CD151 as a high-priority therapeutic target, with relative selectivity (compared with laminin-binding integrins) for pathologic rather than normal physiology.
CD151—A Striking Marker for Cancer Therapy
Cluster of differentiation 151 (CD151) is a member of the mammalian tetraspanin family, which is involved in diverse functions such as maintaining normal cellular integrity, cell-to-cell communication, wound healing, platelet aggregation, trafficking, cell motility and angiogenesis. CD151 also supports de novo carcinogenesis in human skin squamous cell carcinoma (SCC) and tumor metastasis. CD151 interacts with α3β1 and α6β4 integrins through palmitoylation where cysteine plays an important role in the association of CD151 with integrins and non-integrin proteins. Invasion and metastasis of cancer cells were diminished by decreasing CD151 association with integrins. CD151 functions at various stages of cancer, including metastatic cascade and primary tumor growth, thus reinforcing the importance of CD151 as a target in oncology. The present review highlights the role of CD151 in tumor metastasis and its importance in cancer therapy.
2008
CD151, a master regulator of laminin-binding integrins (A 6 B 4 , A 6 B 1 , and A 3 B 1 ), assembles these integrins into complexes called tetraspanin-enriched microdomains. CD151 protein expression is elevated in 31% of human breast cancers and is even more elevated in high-grade (40%) and estrogen receptor-negative (45%) subtypes. The latter includes triplenegative (estrogen receptor, progesterone receptor, and HER2 negative) basal-like tumors. CD151 ablation markedly reduced basal-like mammary cell migration, invasion, spreading, and signaling (through FAK, Rac1, and lck) while disrupting epidermal growth factor receptor (EGFR)-A 6 integrin collaboration. Underlying these defects, CD151 ablation redistributed A 6 B 4 integrins subcellularly and severed molecular links between integrins and tetraspanin-enriched microdomains. In a prototypical basal-like mammary tumor line, CD151 ablation notably delayed tumor progression in ectopic and orthotopic xenograft models. These results (a) establish that CD151-A 6 integrin complexes play a functional role in basallike mammary tumor progression; (b) emphasize that A 6 integrins function via CD151 linkage in the context of tetraspanin-enriched microdomains; and (c) point to potential relevance of CD151 as a high-priority therapeutic target, with relative selectivity (compared with laminin-binding integrins) for pathologic rather than normal physiology.
Cancer Research, 2014
Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins a3b1 and a6b1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151 free ) correlates clinically with tumor progression and metastasis. Clustering CD151 free through its integrin-binding domain promotes accumulation in areas of cell-cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151 free clustering is a strong regulator of motility even in the absence of a3 expression but requires PKCa, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151 free in prostate cancer correlates with poor patient outcome. When CD151 free is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151 free as an independent predictor of survival. Moreover, the detection of CD151 free can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151 free with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression. Cancer Res; 74(1); 173-87. Ó2013 AACR.
The Tetraspanin CD151 Is Required for Met-dependent Signaling and Tumor Cell Growth
Journal of Biological Chemistry, 2010
CD151, a transmembrane protein of the tetraspanin family, is implicated in the regulation of cell-substrate adhesion and cell migration through physical and functional interactions with integrin receptors. In contrast, little is known about the potential role of CD151 in controlling cell proliferation and survival. We have previously shown that 4 integrin, a major CD151 partner, not only acts as an adhesive receptor for laminins but also as an intracellular signaling platform promoting cell proliferation and invasive growth upon interaction with Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF). Here we show that RNAi-mediated silencing of CD151 expression in cancer cells impairs HGF-driven proliferation, anchorage-independent growth, protection from anoikis, and tumor progression in xenograft models in vivo. Mechanistically, we found that CD151 is crucially implicated in the formation of signaling complexes between Met and 4 integrin, a known amplifier of HGF-induced tumor cell growth and survival. CD151 depletion hampered HGF-induced phosphorylation of 4 integrin and the ensuing Grb2-Gab1 association, a signaling pathway leading to MAPK stimulation and cell growth. Accordingly, CD151 knockdown reduced HGF-triggered activation of MAPK but not AKT signaling cascade. These results indicate that CD151 controls Met-dependent neoplastic growth by enhancing receptor signaling through 4 integrin-mediated pathways, independent of cell-substrate adhesion. CD151 is a cell surface protein of the tetraspanin family. These proteins contain four transmembrane domains, two extracellular loops, and two short cytoplasmic tails (1, 2). Tetraspanins are major partners of integrins that regulate cell adhesion to extracellular matrix components as well as cellcell contacts, thereby modulating cell migration. In particular, CD151 is typically associated with ␣31, ␣61, and ␣64 integrin receptor complexes for laminins (3, 4), and its expression is increased during epithelial-mesenchymal transition (5). Not surprisingly, the activity of tetraspanins as pro-migra
CD151 Regulates Tumorigenesis by Modulating the Communication between Tumor Cells and Endothelium
Molecular Cancer Research, 2009
The tetraspanin CD151 forms stoichiometric complexes with laminin-binding integrins (e.g., α3β1, α6β1, and α6β4) and regulates their ligand-binding and signaling functions. We have found that high expression of CD151 in breast cancers is associated with decreased overall survival (3.44-fold higher risk of death). Five-year estimated survival rates were 45.8% (95% confidence interval, 16.4-71.4%) for CD151-positive patients and 79.9% (95% confidence interval, 62.2-90.0%) for CD151-negative patients. Furthermore, CD151 was positively associated with axillary lymph node involvement. To study the biological significance of this observation, we investigated the contribution of CD151 in breast cancer tumorigenesis using MDA-MB-231 cells as a model system. Stable down-regulation of this tetraspanin by short-hairpin RNA decreased the tumorigenicity of these cells in mice. Detailed immunohistologic analysis of CD151 (+) and CD151(−) xenografts showed differences in tumor vascular pattern. Vascularization observed at the subcutaneous border of the CD151(+) tumors was less pronounced or absent in the CD151(−) xenografts. In vitro experiments have established that depletion of CD151 did not affect the inherent proliferative capacity of breast cancer cells in three-dimensional extracellular matrices, but modified their responses to endothelial cells in coculture experiments. The modulatory activity of CD151 was dependent on its association with both α3β1 and α6β4 integrins. These data point to a new role of CD151 in tumorigenesis, whereby it functions as an important regulator of communication between tumor cells and endothelial cells. These results also identify CD151 as a potentially novel prognostic marker and target for therapy in breast cancer. (Mol Cancer Res 2009;7(6):787-98) FIGURE 5. Contribution of fibroblasts and endothelial cells to growth of MDA-MB-231 cells in three-dimensional ECM. Cells embedded in three-dimensional collagen (A) or Matrigel (B and C) were grown above the monolayer of fibroblasts (A and B) or HUVEC (C) as described in the legend to Fig. 4. Bars, 100 μm( A)or50μm(B and C). D. The effect of CD151 depletion on signaling. Serum-starved cells were detached using EDTA and subsequently resuspended in standard growth medium (DMEM/fetal bovine serum) or growth medium conditioned by HUVEC (HUVEC-CM). The cells were plated on Matrigel for the indicated time intervals and then scraped into Laemmli buffer. Proteins were resolved in 10% SDS-PAGE under reduced conditions. The proteins were transferred to a nitrocellulose membrane and probed with the indicated polyclonal antibodies. E. Densitometric analysis of activation Erk1/2 (i.e., measurements of pErk1/2) for the results in D. Measurements were done for two independent experiments (A.D.U., arbitrary densitometry units). Note, the ratios of ∼1.6 (for the 15-min time point) and ∼1.3 (for the 45-min time point) indicate that the presence of CD151 potentiates HUVEC-CM-induced activation of Erk1/2. F. The effect of Src inhibitor on the growth of MDA-MB-231 cells in three-dimensional Matrigel. Cells were embedded in three-dimensional Matrigel and grown for 8 d in HUVEC-CM supplemented with 2 μmol/L of SU6656. The medium was changed every second day. Bar, 50 μm.
Tetraspanin CD151 Regulates Transforming Growth Factor Signaling: Implication in Tumor Metastasis
Cancer Research, 2010
Tetraspanin CD151 is associated with laminin-binding integrins and controls tumor cell migration and invasion. By analyzing responses of breast cancer cells to various growth factors, we showed that depletion of CD151 specifically attenuates transforming growth factor β1 (TGFβ1)-induced scattering and proliferation of breast cancer cells in three-dimensional Matrigel. CD151-dependent cell scattering requires its association with either α3β1o rα6 integrins, but it is independent of the recruitment of CD151 to tetraspanin-enriched microdomains. We also found that CD151 regulates the compartmentalization of TGF-β type I receptor (TβRI/ALK-5) and specifically controls the TGFβ1-induced activation of p38. In contrast, signaling leading to activation of Smad2/3, c-Akt, and Erk1/2 proteins was comparable in CD151(+) and CD151(−) cells. Attenuation of TGFβ1-induced responses correlated with reduced retention in the lung vascular bed, inhibition of pneumocyte-induced scattering of breast cancer cells in three-dimensional Matrigel, and decrease in experimental metastasis to the lungs. These results identify CD151 as a positive regulator of TGFβ1-initiated signaling and highlight the important role played by this tetraspanin in TGFβ1-induced breast cancer metastasis. Cancer Res; 70 ; 6059-70.