CD151 is associated with prostate cancer cell invasion and lymphangiogenesis in vivo

Detchokul, Sujitra; Newell, Bradley; Williams, Elizabeth D.; Frauman, Albert G

doi:10.3892/or.2013.2823

Cited by 20 publications

(17 citation statements)

References 40 publications

(48 reference statements)

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“…Sections were analysed on digitised colour images and evaluated by counting the number of positive staining vessels in five fields within the tumour, chosen at random. Vessels were defined as any brown-staining (DAB immunoperoxidase stain with anti-CD31 antigen) cell cluster clearly separated from any adjacent vessels [ 7 ].…”

Section: Methodsmentioning

confidence: 99%

NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development

et al. 2018

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Reactive oxygen species (ROS) promote growth factor signalling including for VEGF-A and have potent angiogenic and tumourigenic properties. However, the precise enzymatic source of ROS generation, the subcellular localization of ROS production and cellular targets in vivo that influence tumour-promoting processes, are largely undefined. Here, using mRNA microarrays, we show increased gene expression for NOX2, the catalytic subunit of the ROS-generating NADPH oxidase enzyme, in human primary prostate cancer compared to non-malignant tissue. In addition, NOX4 gene expression was markedly elevated in human metastatic prostate cancers, but not in primary prostate tumours. Using a syngeneic, orthotopic mouse model of prostate cancer the genetic deletion of NOX2 (i.e. NOX2-/y mouse) resulted in reduced angiogenesis and an almost complete failure in tumour development. Furthermore, pharmacological inhibition of NOX2 oxidase suppressed established prostate tumours in mice. In isolated endothelial cells, and in human normal and prostate cancer cells, NOX2 co-located to varying degrees with early endosome markers including EEA1, Appl1 and Rab5A and the late endosome marker Rab7A, and this correlated with significant VEGF-A-dependent ROS production within acidified endosomal compartments and endothelial cell proliferation that was NOX2 oxidase- and hydrogen peroxide dependent. We concluded that NOX2 oxidase expression and endosomal ROS production were important for prostate cancer growth and that this was required to positively regulate the VEGF pathway. The research provides a paradigm for limiting tumour growth through a better understanding of NOX2 oxidase's effect on VEGF signalling and how controlling the development of tumour vasculature can limit prostate tumour development and metastasis.

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Section: Methodsmentioning

confidence: 99%

NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development

et al. 2018

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“…The tetraspanins are also involved in cell proliferation and tissue vascularization [37] , [38] , [60] , [61] . CD151 is highly expressed in several cancers, including gastric, endometrial, liver, breast, prostate, and glioma [9] , [10] , [52] , [55] , [56] . Its aberrant expression is associated with multiple oncogenic activities such as metastasis and angiogenesis [8] , [10] .…”

Section: Introductionmentioning

confidence: 99%

Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151

et al. 2016

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Glioblastoma (GBM) stem cells (GSCs) represent tumor-propagating cells with stem-like characteristics (stemness) that contribute disproportionately to GBM drug resistance and tumor recurrence. Understanding the mechanisms supporting GSC stemness is important for developing therapeutic strategies for targeting GSC-dependent oncogenic mechanisms. Using GBM-derived neurospheres, we identified the cell surface tetraspanin family member CD151 as a novel regulator of glioma cell stemness, GSC self-renewal capacity, migration, and tumor growth. CD151 was found to be overexpressed in GBM tumors and GBM neurospheres enriched in GSCs. Silencing CD151 inhibited neurosphere forming capacity, neurosphere cell proliferation, and migration and attenuated the expression of markers and transcriptional drivers of the GSC phenotype. Conversely, forced CD151 expression promoted neurosphere self-renewal, cell migration, and expression of stemness-associated transcription factors. CD151 was found to complex with integrins α3, α6, and β1 in neurosphere cells, and blocking CD151 interactions with integrins α3 and α6 inhibited AKT phosphorylation, a downstream effector of integrin signaling, and impaired sphere formation and neurosphere cell migration. Additionally, targeting CD151 in vivo inhibited the growth of GBM neurosphere-derived xenografts. These findings identify CD151 and its interactions with integrins α3 and α6 as potential therapeutic targets for inhibiting stemness-driving mechanisms and stem cell populations in GBM.

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“…Claudin-20, for example, a tight junction protein in the epithelium, is correlated with poor prognosis of breast cancer patients, likely through its increased migratory effect on cancer cells [ 38 ]. CD151 is correlated with poor prognosis in endometrial cancer [ 39 ], accelerates breast cancer cell invasion via integrin α6 [ 40 ], and promotes prostate cancer migratory activity and lymphangiogenesis, increasing metastatic potential [ 41 ]. Based on these studies and our findings, targeting of the tetra-spanning membrane proteins, including EMP1, may reduce the malignancy of cancer cells, leading to the development of novel anti-cancer therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac1

et al. 2018

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Tumor metastasis is the most common cause of cancer death. Elucidation of the mechanism of tumor metastasis is therefore important in the development of novel, effective anti-cancer therapies to reduce cancer mortality. Interaction between cancer cells and surrounding stromal cells in the tumor microenvironment is a key factor in tumor metastasis. Using a co-culture assay system with human prostate cancer LNCaP cells and primary human prostate stromal cells, we identified epithelial membrane protein 1 (EMP1) as a gene with elevated expression in the cancer cells. The orthotopic injection of LNCaP cells overexpressing EMP1 (EMP1-LNCaP cells) into the prostate of nude mice induced lymph node and lung metastases, while that of control LNCaP cells did not. EMP1-LNCaP cells had higher cell motility and Rac1 activity than control LNCaP cells. These results were also observed in other lines of cancer cells. We newly identified copine-III as an intracellular binding partner of EMP1. Knockdown of copine-III attenuated the increased cell motility and Rac1 activity in EMP1-LNCaP cells. Reduced cell motility and Rac1 activity following knockdown of copine-III in EMP1-LNCaP cells were recovered by re-expression of wild-type copine-III, but not of a copine-III mutant incapable of interacting with EMP1, suggesting the importance of the EMP1–copine-III interaction. Phosphorylated and activated Src and a Rac guanine nucleotide exchange factor Vav2 were found to be involved in the EMP1-induced enhancement of cell motility and Rac1 activation. Moreover, EMP1 was highly expressed in prostate cancer samples obtained from patients with higher Gleason score. These results demonstrate that upregulation of EMP1 significantly increases cancer cell migration that leads to tumor metastasis, suggesting that EMP1 may play an essential role as a positive regulator of tumor metastasis.

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CD151 is associated with prostate cancer cell invasion and lymphangiogenesis in vivo

Cited by 20 publications

References 40 publications

NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development

NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development

Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151

Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac1

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