A role for heterologous gap junctions between melanoma and endothelial cells in metastasis

Ito, Akihiko; Katoh, Fumitaka; Kataoka, Tatsuki R.; Okada, Morihito; Tsubota, Noriaki; Asada, Hideo; Yoshikawa, Kunihiko; Maeda, Sakan; Kitamura, Yukihiko; Yamasaki, Hiroshi; Nishimura, Hiroshi

doi:10.1172/jci8257

Cited by 171 publications

(199 citation statements)

References 37 publications

Supporting

Mentioning

188

Contrasting

Unclassified

Order By: Relevance

“…E-cadherin and its associated catenin complex (26), as well as Connexin 26, through heterologous gap junction formation with endothelial cells (27), play a crucial role in intravasation and extravasation of tumor cells. The potential modulation of homotypic and heterotypic cell interactions by ANGPTL4 therefore requires further investigations.…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness

Galaup

Cazes

Jan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

226

219

View full text Add to dashboard Cite

Angiopoietin-like 4 (ANGPTL4), a secreted protein of the angiopoietin-like family, is induced by hypoxia in both tumor and endothelial cells as well as in hypoxic perinecrotic areas of numerous cancers. Here, we investigated whether ANGPTL4 might affect tumor growth as well as metastasis. Metastatic 3LL cells were therefore xenografted into control mice and mice in which ANGPTL4 was expressed by using in vivo DNA electrotransfer. Whereas primary tumors grew at a similar rate in both groups, 3LL cells metastasized less efficiently to the lungs of mice that expressed ANGPTL4. Fewer 3LL emboli were observed in primary tumors, suggesting that intravasation of 3LL cells was inhibited by ANGPTL4. Furthermore, melanoma B16F0 cells injected into the retro-orbital sinus also metastasized less efficiently in mice expressing ANGPTL4. Although B16F0 cells were observed in lung vessels, they rarely invaded the parenchyma, suggesting that ANGPTL4 affects extravasation. In addition, recombinant B16F0 cells that overexpress ANGPTL4 were generated, showing a lower capacity for in vitro migration, invasion, and adhesion than control cells. Expression of ANGPTL4 induced reorganization of the actin cytoskeleton through inhibition of actin stress fiber formation and vinculin localization at focal contacts. Together, these results show that ANGPTL4, through its action on both vascular and tumor compartments, prevents the metastatic process by inhibiting vascular activity as well as tumor cell motility and invasiveness.angiogenesis ͉ cancer ͉ hypoxia

show abstract

Section: Discussionmentioning

confidence: 99%

Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness

Galaup

Cazes

Jan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

226

219

View full text Add to dashboard Cite

show abstract

“…A connexon composed of heterogeneous Cx subtypes partly forms at the gap junction, resulting in a heterotypic gap junction. It has been reported that depending on the expression level of Cx subtypes, an abnormal cell transduction system between stromal cells of the host and the cancer cells is formed and induces phenotypic transformation of the host stromal cells resulting in the induction of the invasion of cancer cells (22,30). In addition, it has been speculated that by controlling the expression of genes acting on the growth and differentiation of cells, Cx controls the progression of tumors (25).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that Cx26 forms a heterologous gap junction with endothelial cells of the blood vessels in the vicinity of tumors, and thus facilitates the intravasation and extravasation of tumors and controls the invasion of the metastatic potential of tumor cells (22). Hence, it appears that the actual role of Cx and the gap junction may be different depending on tumor type and stage of progression.…”

Section: Introductionmentioning

confidence: 99%

Pathological significance of connexin 26 expression in colorectal adenocarcinoma

Ren

Lim²

2008

Oncol Rep

View full text Add to dashboard Cite

Abstract. This study was conducted to determine the level of expression and cellular localization of connexin 26 (Cx26) and the expression of p53 in colorectal adenocarcinoma as well as their relationship to clinicopathological features. Immunohistochemical staining was performed in 130 colorectal adenocarcinoma cases. A correlation between the expression levels of the two proteins and an analysis of the clinicopathological features of the samples was performed. There was a statistical significant difference in the Cx26 expression level among normal epithelium (NE), adenomas and adenocarcinomas (p<0.001). Of the 130 adenocarcinomas, 48.5% were positive for Cx26. All of the adenoma and NE samples were positive for Cx26 expression; however, the level of expression of Cx26 in adenomas was smaller than the level of expression for NE. Cytoplasmic staining for Cx26 was observed in the adenocarcinomas (23.8%), but was not observed in the adenoma and NE samples. A positive correlation between a reduction in intercellular Cx26 and tumor invasion was statistically significant (p<0.05). Expression of p53 was positive for 50% of the adenocarcinomas, and the level of p53 was increased in a reverse proportion to the level of Cx26 intercellular staining. In conclusion, loss of intercellular and gain of intracytoplasmic Cx26 expression may play a role in colorectal carcinogenesis and tumor progression.

show abstract

“…Much remains to be learned about how the specific combination of connexins facilitates tissue interactions, but it is clear, again, that generalizations should be avoided, as the expression patterns (and probably the function) of connexins are tissue dependent and change during tumour progression 17,18 . For example, some breast cancer cells upregulate connexin 32 (Cx32) 19 , but loss of Cx32 contributes to hepatocellular carcinoma 20,21 ; Cx43 inhibits tumorigenicity of lung, cervical and bladder carcinoma cells [22][23][24] , but has no effect on squamous cell carcinomas 25 ; and other connexins can facilitate cell adhesion during metastasis 26 .…”

Section: Box 1 Epithelial Cell Polarity and Tumorigenesis In Drosophilamentioning

confidence: 99%

Putting tumours in context

2001

View full text Add to dashboard Cite

The interactions between cancer cells and their micro-and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.Under normal conditions, ORGANS are made up of TISSUES that exchange information with other cell types via cell-cell contact, cytokines and the EXTRACELLULAR MATRIX (ECM). The ECM, which is produced by collaboration between STROMAL fibroblasts and EPITHELIAL cells, provides structural scaffolding for cells, as well as contextual information. The endothelial vasculature provides nutrients and oxygen, and cells of the immune system combat pathogens and remove apoptotic cells. Epithelial cells associate into intact, polarized sheets. These tissues communicate through a complex network of interactions: physically, through direct contact or through the intervening ECM, and biochemically, through both soluble and insoluble signalling molecules. In combination, these interactions provide the information that is necessary to maintain cellular differentiation and to create complex tissue structures.Occasionally, the intercellular signals that define the normal context become disrupted. Alterations in epithelial tissues can lead to movement of epithelial sheets and proliferationfor example, after activation of mesenchymal fibroblasts due to wounding. Normally, these conditions are temporary and reversible, but when inflammation is sustained, an escalating feedback loop ensues. Under persistent inflammatory conditions, continual upregulation of enzymes such as matrix metalloproteinases (MMPs) by stromal fibroblasts can disrupt the ECM, and invading immune cells can overproduce factors that promote abnormal proliferation.As this process progresses, the normal organization of the organ is replaced by a functional disorder (FIG. 1). If there are pre-existing epithelial cells within this changing context that possess tumorigenic potential, they can start to proliferate. Alternatively, the abnormal An innate anticancer mechanismAn important feature of the normal stromal context is the generation and maintenance of epithelial-cell polarity. Epithelial cells receive a variety of orientational cues from the environment that help them establish cellular apical and basal surfaces and to maintain the differentiated state. Loss of polarity has been shown to lead to increased cell proliferation and tumorigenesis (BOX 1). The basal surface of epithelial cells associates with the BASEMENT MEMBRANE, a specialized form of ECM that provides both structural support and polarization signals to epithelia. The basement membrane is a dynamic structure. Changes in its composition lead to changes in cell shape and behaviour 1 , altered binding affinity or cellular distribution of cell-surface receptors 2 , and cellu...

show abstract

A role for heterologous gap junctions between melanoma and endothelial cells in metastasis

Cited by 171 publications

References 37 publications

Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness

Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness

Pathological significance of connexin 26 expression in colorectal adenocarcinoma

Putting tumours in context

Contact Info

Product

Resources

About