Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene

Saito, Tsuyoshi; Krutovskikh, Vladimir; Marion, Marie‐Jeanne; Ishak, Kamal G.; Bennett, William P.; Yamasaki, Hiroshi

doi:10.1002/(sici)1097-0215(20000401)86:1<67::aid-ijc10>3.0.co;2-1

Cited by 21 publications

(10 citation statements)

References 26 publications

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“…This finding suggests that Cx37 activity may also require regulation by the Cx37 COOH-terminus, which contains predicted binding sites for growth-related kinases PKC and MAPK (21). Interestingly, the S319P polymorphism has also been associated with an altered incidence of hemangiosarcoma, a highly invasive endothelium-derived can-cer, in human patients (25). Taken together, these studies suggest that both an intact Cx37 channel domain, as well as regulatory domains located in the Cx37 COOH-terminus, might be required for Cx37 to limit endothelial proliferation.…”

Section: Resultsmentioning

confidence: 99%

Cx37 deletion enhances vascular growth and facilitates ischemic limb recovery

Fang

Angelov

Simon

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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The unique contributions of connexin (Cx)37 and Cx40, gap junction-forming proteins that are coexpressed in vascular endothelium, to the recovery of tissues from ischemic injury are unknown. We recently reported that Cx37-deficient (Cx37(-/-)) animals recovered ischemic hindlimb function more quickly and to a greater extent than wild-type (WT) or Cx40(-/-) animals, suggesting that Cx37 limits recovery in the WT animal. Here, we tested the hypothesis that enhanced angiogenesis, arteriogenesis, and vasculogenesis contribute to improved postischemic hindlimb recovery in Cx37(-/-) animals. Ischemia was induced unilaterally in the hindlimbs of WT or Cx37(-/-) mice (isoflurane anesthesia). Postsurgical limb appearance, use, and perfusion were documented during recovery, and the number (and size) of large and small vessels was determined. Native collateral number, predominantly established during embryonic development (vasculogenesis), was also determined in the pial circulation. Both microvascular density in the gastrocnemius of the ischemic limb (an angiogenic field) and the number and tortuosity of larger vessels in the gracilis vasculature (an arteriogenic field) were increased in Cx37(-/-) animals compared with WT animals. Cx37(-/-) mice also had an increased (vs. WT) number of collateral vessels in the pial circulation. These findings suggest that in Cx37(-/-) animals, improved recovery of the ischemic hindlimb involves enhanced vasculogenesis, resulting in increased numbers of collaterals in the hindlimb (and pial circulations) and more extensive collateral remodeling and angiogenesis. These results are consistent with Cx37 exerting a growth-suppressive effect in the vasculature that limits embryonic vasculogenesis as well as arteriogenic and angiogenic responses to ischemic injury in the adult animal.

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Section: Resultsmentioning

confidence: 99%

Cx37 deletion enhances vascular growth and facilitates ischemic limb recovery

Fang

Angelov

Simon

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Multiple mechanisms appear to be responsible for this (Yamasaki and Naus, 1996), but mutations have not previously been shown to be among them. However, it is worth noting that only a few individual connexins, namely Cx32 in hepatocellular carcinomas (Krutovskikh et al, 1994) and Cx37 in lung and endothelial human and rodent tumors (Krutovskikh et al, 1996;Saito et al, 1997Saito et al, , 2000 were examined on mutations. It appears that the tumor-suppressive capacity of individual connexins is very connexin-species and tissue-specific.…”

mentioning

confidence: 76%

Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer

et al. 2002

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The membrane-spanning connexin proteins form microscopic intercellular channels that directly connect the cytoplasms of adjacent cells and as such have been implicated in maintenance of tissue homeostasis. They are considered to act as tumor suppressors since their function or expression is frequently aberrant in tumor cells. Several mechanisms appear to be involved in this, but irreversible mutational alterations have not yet been proved to be among them. In this study we have demonstrated for the first time that connexin 43 but not connexin 32 is specifically and quite frequently mutated in human colon sporadic adenocarcinomas. All tumor-associated mutations led to a shift of reading frame and were located in the multifunctional carboxylterminal domain of the protein. Expression of mutated connexin 43 protein was restricted to invasive structures of tumors. These findings suggest that mutational alterations of connexin 43 are involved in advanced stages of progression of human colon cancer towards malignancy.

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“…Although Cx37 gene mutations in two murine Lewis lung carcinoma cell lines induced tumor-associated antigens, no mutation of Cx37 gene has been detected in these cell lines [155,156]. In human hepatic angiosarcomas, no Cx37 gene mutation has been detected, but a polymorphism that occurs at codon 319, a site of phosphorylation for some protein kinases, might explain why GJIC is impaired in most angiosarcomas [157]. In these studies, no mutation of other Cx genes has been reported.…”

Section: Connexin Gene Mutationmentioning

confidence: 99%

Connexins as Precocious Markers and Molecular Targets for Chemical and Pharmacological Agents in Carcinogenesis

Pointis

Fiorini²,

Gilleron³

et al. 2007

CMC

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Gap junctions, intercellular channels structured by the connexin protein family, have been implicated in the control of cell homeostasis, proliferation, differentiation and death. A loss of the gap junction intercellular communication and/or connexin dysfunction are typical features of cancer per se and have been associated with the effect of many carcinogens. Indeed, many early human neoplasia of various organs and human tumor cell lines exhibit deficient connexin-mediated communication expression mainly related, in a large number of observations, with an aberrant cytoplasmic localization of this membranous protein. Restoration of normal phenotype in transformed cells by restoration of exogenous connexin gave rise to the concept that connexins may act as tumor suppressors. However, the mechanisms by which connexins mediate such a tumor suppressor effect are multiple. They may result from: formation of functional channels; hemichannels or are directly associated with connexin expression. In addition, the literature shows that they may be dependent upon the cell type and the connexin type. In the present review, we analyze all these aspects of connexin/gap junction involvement in the carcinogenesis process, in human cancers and discuss the possibility of using connexins as potential anti-oncogenic targets for cancer chemoprevention and/or chemotherapy.

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Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene

Cited by 21 publications

References 26 publications

Cx37 deletion enhances vascular growth and facilitates ischemic limb recovery

Cx37 deletion enhances vascular growth and facilitates ischemic limb recovery

Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer

Connexins as Precocious Markers and Molecular Targets for Chemical and Pharmacological Agents in Carcinogenesis

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