Regulation of CD151 by Hypoxia Controls Cell Adhesion and Metastasis in Colorectal Cancer

Abstract

Purpose: The first step of metastasis is the detachment of cancer cells from the surrounding matrix and neighboring cells; however, how cancer cells accomplish this process remains unclear. Thus, we aimed to investigate the underlying mechanism that controls the early event of metastasis. Experimental Design: One hundred and thirty-seven paired colorectal carcinoma and normal colon tissues were examined by immunohistochemical staining and Western blot for the expression of CD151, a member of the tetraspanin family that plays important roles in cell adhesion and motility. The effect of CD151 on cancer cell adhesion was investigated under normoxia and hypoxia conditions. Results: The level of CD151 was down-regulated in colon cancer compared with the paired normal counterparts. Expression of CD151was negatively regulated by hypoxia inducible factor1^dependent hypoxic stress. Suppression of CD151by hypoxia caused the detachment of cancer cells from the surrounding matrix and neighboring cells whereas restoration of CD151expression during reoxygenation facilitated the adhesion capacity. Clinical examination further showed that metastasized cancer cells expressed a greater level of CD151 compared with that of primary tumor. Conclusion: Regulation of CD151 by oxygen tension may play an important role in cancer metastasis by regulating the detachment from the primary site and homing in the secondary site.Cancer metastasis is a complex, multistep process with mechanisms largely unknown despite intensive investigation in the past. The first step of metastasis is the detachment of cancer cells from the surrounding matrix and neighboring cells. Adhesions between normal epithelial cells and cell-matrix are strong so local cell invasion is not able to occur. Therefore, the necessary early event in cancer invasion and metastasis is the conversion of the stationary phenotype to the migratory phenotype. This can be achieved by down-regulation of cell adhesion molecules such as cadherins and integrins. Indeed, studies have revealed that loss or down-regulation of E-cadherin and one or more of the integrins is a common feature of several epithelial malignancies (1, 2). Nonetheless, the underlying mechanisms of causing the down-regulation of these molecules are not yet clear. In addition, whether there are other molecules that also control cancer cell adhesion needs to be elucidated.Many factors have been identified as playing important roles in the regulation of cancer metastasis. Among these, hypoxia is the most common and critical one. Because oxygen can only diffuse for 150 to 200 Am, cells will face the hypoxic stress when distances of cells from a capillary exceed this range. Owing to the rapid growing nature, cancer cells of solid tumors frequently encounter reduced oxygen tension. The hypoxic stress will force cancer cells to develop necessary processes such as induction of angiogenesis, metabolic switch, and migration to avoid cell death. These responses to hypoxia are mainly mediated through genes regulated by t...

Immune Escape and Survival Mechanisms in Circulating Tumor Cells of Colorectal Cancer

“…This, again, may indicate the shortlived nature of the phenotypic changes in CTC: once in circulation, CTC do not require migratory capabilities anymore and may have already lost the mesenchymal phenotype at the time of analysis. Consequently, the tetraspanin CD151, which is involved in cell-cell contacts and which has been shown to be downregulated in metastatic colorectal cancer as compared with nonmetastatic colorectal cancer (40,41), was significantly downregulated, indicating reduced cell-cell adhesion capabilities of CTC. The blood stream is a hostile environment for tumor cells; although a tumor presumably sheds millions of tumor cells into the blood stream every day (42), only few can be detected at any given time.…”

Suppression of dual-specificity phosphatase–2 by hypoxia increases chemoresistance and malignancy in human cancer cells

“…Cancer cells were cultured in medium containing 10% FBS and antibiotics (100 μg/ml streptomycin and 100 U/ml penicillin G) in a humidified atmosphere of 5% CO2 and 95% air at 37°C. SW480 cells were cultured in the absence of CO2 as previously described (46). When cells reached 70% confluence, cultured medium was changed to serum-free medium for 16 hours.…”

“…Ethics approval for human studies was obtained from the Clinical Research Ethics Committee at National Cheng Kung University Medical Center, and informed consent was given by each patient. The procedure used for immunohistochemical staining was described previously (46).…”

CD151 in cancer progression and metastasis: a complex scenario

“…Moreover, its expression in malignant cells was downregulated when compared with normal adjacent tissue. 9,78 No association with disease progression was demonstrated in either oral SCC or epithelial ovarian tumours by immunochemical and transcriptional analysis, respectively. 79,80 The ability of CD151 to enhance primary tumour growth and promote cancer cell invasion and migration in vitro has aroused an interest in its potential contribution to metastasis.…”

“…Its role in promotion of invasion and migration has been demonstrated in numerous in vitro and in vivo models. [6][7][8][9][10] CD151 was found to participate in nearly all stages of cancer progression. Its involvement in the early events of tumour development was demonstrated in diverse biological contexts.…”