Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways

Arbiser, Jack L.; Moses, Marsha A.; Fernández, Cecilia A.; Ghiso, N; Cao, Yihai; Klauber, Nancy; Frank, David A.; Brownlee, Michael; Flynn, Evelyn; Parangi, Sareh; Byers, H. Randolph; Folkman, Judah

doi:10.1073/pnas.94.3.861

Cited by 419 publications

(344 citation statements)

References 41 publications

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“…ROCK1 & 2 are ubiquitously expressed protein kinases. To demonstrate the expression of these paralogs in MILE SVEN 1 (MS1) pancreatic islet endothelial cells, which is a well established mouse endothelial line previously developed in Judah Folkman’s laboratory [24], we performed Western analysis to reveal that both ROCK1 & 2 are present at detectable levels (Fig. 1A ).…”

Section: Resultsmentioning

confidence: 99%

Rock1 & 2 Perform Overlapping and Unique Roles in Angiogenesis and Angiosarcoma Tumor Progression

Montalvo¹,

Spencer²,

Hackathorn³

et al. 2012

CMM

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The serine/threonine protein kinase paralogs ROCK1 & 2 have been implicated as essential modulators of angiogenesis; however their paralog-specific roles in endothelial function are unknown. shRNA knockdown of ROCK1 or 2 in endothelial cells resulted in a significant disruption of in vitro capillary network formation, cell polarization, and cell migration compared to cells harboring non-targeting control shRNA plasmids. Knockdowns led to alterations in cytoskeletal dynamics due to ROCK1 & 2-mediated reductions in actin isoform expression, and ROCK2-specific reduction in myosin phosphatase and cofilin phosphorylation. Knockdowns enhanced cell survival and led to ROCK1 & 2-mediated reduction in caspase 6 and 9 cleavage, and a ROCK2-specific reduction in caspase 3 cleavage. Microarray analysis of ROCK knockdown lines revealed overlapping and unique control of global transcription by the paralogs, and a reduction in the transcriptional regulation of just under 50% of VEGF responsive genes. Finally, paralog knockdown in xenograft angiosarcoma tumors resulted in a significant reduction in tumor formation. Our data reveals that ROCK1 & 2 exhibit overlapping and unique roles in normal and dysfunctional endothelial cells, that alterations in cytoskeletal dynamics are capable of overriding mitogen activated transcription, and that therapeutic targeting of ROCK signaling may have profound impacts for targeting angiogenesis.

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Section: Resultsmentioning

confidence: 99%

Rock1 & 2 Perform Overlapping and Unique Roles in Angiogenesis and Angiosarcoma Tumor Progression

Montalvo¹,

Spencer²,

Hackathorn³

et al. 2012

CMM

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“…It is known that down regulation of p21-ras causes a decrease of vascular endothelial growth factor (VEGF) production (Arbiser et al, 1997;Okada et al, 1998;Zhang et al, 2001). A bystander effect caused by down regulation of VEGF after p53-gene therapy in vivo has already been described (Bouvet et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras

et al. 2002

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Ras mutations are present in 40 -50% of colorectal cancers. Inactivating this oncogene may therefore reduce proliferation capacity. In order to target ras we studied the transduction efficacy and anti tumour activity of an adenoviral vector expressing an intracellular, neutralizing single chain antibody to p21-ras (Y28). In in vitro studies transfection levels of the K-ras mutated rat colon carcinoma cell line CC531 were studied using the LacZ marker gene. In our in vivo liver metastases model different routes of administration were evaluated to determine which regimen resulted in the best transfection levels and tumour responses: intravenous injection, intratumoural injection, isolated liver perfusion, or hepatic artery infusion. CC531 cells are readily transfected in vitro, resulting in significant inhibition of tumour cell proliferation by the Y28 construct. Intravenous injection did not result in any measurable transfection. Intratumoural injection resulted only in the transfection of tumour cells along the needle track. IHP as well as single HAI achieved low transfection levels of tumour tissue. Expression of Y28 was demonstrated in tumours after IT injection, HAI and IHP. Whereas, repeated HAI's clearly achieved expression in and around tumour associated vessels. Only five times repeated HAI's with Y28 resulted in a tumour response: in all animals tumour growth was inhibited, and in three rats out of eight a complete regression of the liver tumours was observed.

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“…SVR cells, an immortalised murine endothelial cell line over expressing H-ras, form angiosarcoma tumours in vivo [128]. In vitro studies with SVR cells showed that downregulation of MEK (MAPKK), by using clones with dominant negative MEK or by inhibition of MEK with the drug PD98059, resulted in a significant reduction in colony formation [129].…”

Section: Abnormal Growth Signalsmentioning

confidence: 99%

“…pathway in SVR cells did result in significantly smaller angiosarcoma tumours in vivo [128], although independent over expression of Akt1 in murine endothelial cells resulted in benign vascular malformations distinct from angiosarcomas [130]. The viral oncogene v-p3k, of the avian sarcoma virus ASV16, codes for a gene homologous to the catalytic subunit of PI-3-kinase.…”

Section: Abnormal Growth Signalsmentioning

confidence: 99%