Restoration of caveolin-1 expression suppresses growth and metastasis of head and neck squamous cell carcinoma

Abstract

Caveolin-1 (Cav-1) plays an important role in modulating cellular signalling, but its role in metastasis is not well defined. A significant reduction in Cav-1 levels was detected in lymph node metastases as compared with primary tumour of head and neck squamous cell carcinoma (HNSCC) specimens (P<0.0001), confirming the downregulation of Cav-1 observed in a highly metastatic M4 cell lines derived from our orthotopic xenograft model. To investigate the function of Cav-1 in metastasis of HNSCC, we compared stable clones of M4 cells carrying human cav-1 cDNA (CavS) with cells expressing an empty vector (EV) in vitro and in the orthotopic xenograft model. Overexpression of Cav-1 suppressed growth of the CavS tumours compared with the EV tumours. The incidence of lung metastases was significantly lower in animals carrying CavS tumours than those with EV tumours (P=0.03). In vitro, CavS cells displayed reduced cell growth, invasion, and increased anoikis compared with EV cells. In CavS cells, Cav-1 formed complex with integrin β1 and Src. Further application of integrin β1 neutralising antibody or Src inhibitor PP2 to EV cells illustrated similar phenotypes as CavS cells, suggesting that Cav-1 may play an inhibitory role in tumorigenesis and lung metastasis through regulating integrin β1- and Src-mediated cell–cell and cell–matrix interactions.

Caveolin-1 promotes pancreatic cancer cell differentiation and restores membranous E-cadherin via suppression of the epithelial-mesenchymal transition

“…5,38 Our current results show that Cav-1 expression greatly blocks tumor formation in an in vivo xenograft model. More interestingly, Cav-1 expressing tumors displayed nests of differentiated cells, which were completely absent in control …”

“…As a consequence, many studies recognize Cav-1 as a modulator of cell transformation, proliferation and metastasis. 4,5 Depending on the tissue context, Cav-1 can act either as a tumor suppressor, for example in pulmonary, 6,7 mammary, 8,9 colon 10 and ovarian 11 cancers, or as a tumor promoter, for example in prostate, 12 bladder 13 and renal 14 cancers.…”

Differential expression and function of the caveolin-1 gene in non-small cell lung carcinoma

“…The role of Cav-1 in cancer cells is still debated and highly controversial. Cav-1 is down-regulated, e.g., in human ovarian carcinoma (5), colon AC (6) and head and neck SCC (7), this function strongly suggests the possible role of Cav-1 as a tumor suppressor. Consistent with this, the human caveolin gene is mapped to a suspected tumor locus (7q31.1), which is often deleted in human cancers (8).…”

The Caveolin-1 Connection to Cell Death and Survival

“…Many of these interactions, such as those with the epidermal growth factor receptor, Src kinases, the Ras/Raf/MAPK pathway, PKCs and endothelial nitric oxide synthase (eNOS), occur via the scaffolding domain of Caveolin-1 (CSD; amino acids [82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101] and the scaffolding domain binding domain (CBD) found in the respective target proteins [3]. However, as highlighted in Fig.…”

“…Also, in Caveolin-1 knock-out mice, signaling via the MAPK/ERK pathway is increased and associated with increased sensitivity to topically applied carcinogens, cardiac hypertrophy and neointimal hyperplasia [33,[87][88]. Moreover, in human head and neck squamous cell cancer, Caveolin-1 inhibits the ERK pathway and cell growth [89], and in human laryngeal carcinoma cell lines, Caveolin-1 interaction with the EGFR is associated with reduced MAPK/ERK phosphorylation and increased apoptotic cell death [90].…”