Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma.

Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma. Research Abstract Details 

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Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma. Abstract Text:

Shioto Suzuki,Carl-Henrik Heldin,Rainer Lothar Heuchel,

BACKGROUND: Platelet-derived growth factor (PDGF)-BB and PDGF receptor (PDGFR)-beta are mainly expressed in the developing vasculature, where PDGF-BB is produced by endothelial cells and PDGFR-beta is expressed by mural cells, including pericytes. PDGF-BB is produced by most types of solid tumors, and PDGF receptor signaling participates in various processes, including autocrine stimulation of tumor cell growth, recruitment of tumor stroma fibroblasts, and stimulation of tumor angiogenesis. Furthermore, PDGF-BB-producing tumors are characterized by increased pericyte abundance and accelerated tumor growth. Thus, there is a growing interest in the development of tumor treatment strategies by blocking PDGF/PDGFR function. We have recently generated a mouse model carrying an activated PDGFR-beta by replacing the highly conserved aspartic acid residue (D) 849 in the activating loop with asparagine (N). This allowed us to investigate, in an orthotopic tumor model, the role of increased stromal PDGFR-beta signaling in tumor-stroma interactions. METHODS: B16 melanoma cells lacking PDGFR-beta expression and either mock-transfected or engineered to express PDGF-BB, were injected alone or in combination with matrigel into mice carrying the activated PDGFR-beta (D849N) and into wild type mice. The tumor growth rate was followed and the vessel status of tumors, i.e. total vessel area/tumor, average vessel surface and pericyte density of vessels, was analyzed after resection. RESULTS: Tumors grown in mice carrying an activated PDGFR-beta were established earlier than those in wild-type mice. In this early phase, the total vessel area and the average vessel surface were higher in tumors grown in mice carrying the activated PDGFR-beta (D849N) compared to wild-type mice, whereas we did not find a significant difference in the number of tumor vessels and the pericyte abundance around tumor vessels between wild type and mutant mice. At later phases of tumor progression, no significant difference in tumor growth rate was observed between wild type mice and mutant mice, although the pericyte coverage was higher around tumor vessels from mutant mice. CONCLUSION: Our findings suggest that the activated PDGFR-beta (D849N) in the host animal increased the total vessel area and the average vessel surface even in PDGF-negative tumors, resulting in a shorter lag phase during tumor establishment.

Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma. Publishing Authors By Initials

S Suzuki,CH Heldin,RL Heuchel,

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Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: BMC cancer

VOLUME: 7

Page Numbers: 224

Journal Abbreviation: BMC Cancer

ISSN: 1471-2407

DAY: 12

MONTH: 12

YEAR: 2007

Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma. Information

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LANGUAGE: eng

NlmUniqueID: 100967800

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AFFILIATION: Ludwig Institute for Cancer Research, Uppsala Branch, Uppsala, Sweden. shiosuzuki-path@umin.net

Country: England

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MEDLINETA: BMC Cancer

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