Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

• Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

hereditary hemorrhagic telangiectasia

pancreatic neuroendocrine tumors

tgf-beta-receptor

anti-angiogenic therapy

renal-cell carcinoma

human

solid tumors

antiangiogenic therapy

growth-factor

mouse model

heterozygous mice

Simmons

Brett H.Simmons

BHLippincott

JohnLippincott

JCasperson

Gerald F.Casperson

GFLevin

LIVERYnullEscudier

BernardEscudier

BEisen

TimEisen

TStadler

Walter M.Stadler

WMSzczylik

VELOPMENTnullPerez-Gomez

EduardoDel Castillo

GaelleJuan Francisco

SantibanezLopez-Novoa

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Publication and Content Type

ref (subject category)

art (subject category)