The liver is a common host organ for cancer, either through lesions that arise in liver epithelial cells [e.g., hepatocellular carcinoma (HCC)] or as a site of metastasis by tumors arising in other organs (e.
View Article and Find Full Text PDFAngiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here, we characterized by single-cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling.
View Article and Find Full Text PDFAnti-VEGF therapies benefit several cancer types, but drug resistance that limits therapeutic response can emerge. We generated cell lines from anti-VEGF-resistant tumor xenografts to investigate the mechanisms by which resistance develops. Of all tumor cells tested, only A431 (A431-V) epidermoid carcinoma cells developed partial resistance to the VEGF inhibitor aflibercept.
View Article and Find Full Text PDFVascular endothelial growth factor (VEGF) is a key upstream mediator of tumor angiogenesis, and blockade of VEGF can inhibit tumor angiogenesis and decrease tumor growth. However, not all tumors respond well to anti-VEGF therapy. Despite much effort, identification of early response biomarkers that correlate with long-term efficacy of anti-VEGF therapy has been difficult.
View Article and Find Full Text PDFThe angiopoietins Ang1 (ANGPT1) and Ang2 (ANGPT2) are secreted factors that bind to the endothelial cell-specific receptor tyrosine kinase Tie2 (TEK) and regulate angiogenesis. Ang1 activates Tie2 to promote blood vessel maturation and stabilization. In contrast, Ang2, which is highly expressed by tumor endothelial cells, is thought to inhibit Tie2 activity and destabilize blood vessels, thereby facilitating VEGF-dependent vessel growth.
View Article and Find Full Text PDFTwo vascular systems, cardiovascular and lymphatic, maintain appropriate interstitial and intravascular fluid volume in the body. Each is endowed with innate physiologic response capabilities activated upon tissue or organ "damage." Chronic activation following pathologic assault, however, can contribute to pathogenesis.
View Article and Find Full Text PDFBlood and lymphatic vasculature are essential components of all organs, responsible for maintaining organ fluid dynamics and tissue homeostasis. Although both vessel systems are composed of similar lineages of endothelial cells whose crude functions include fluid and cell transport, each system also possesses distinctive physiologic properties, enabling their distinctive functions in tissues. The role of hematogenous vasculature and development of angiogenic blood vessels during cancer development is well established; however, the role of lymphangiogenesis and structural/functional alterations occurring within lymphatic vessels during cancer development are incompletely understood.
View Article and Find Full Text PDFRecessive inactivating mutations in human matrix metalloproteinase 2 (MMP2, gelatinase A) are associated with syndromes that include abnormal facial appearance, short stature, and severe bone loss. Mmp2(-/-) mice have only mild aspects of these abnormalities, suggesting that MMP2 function is redundant during skeletal development in the mouse. Here, we report that Mmp2(-/-) mice with additional mutations that render type I collagen resistant to collagenase-mediated cleavage to TC(A) and TC(B) fragments (Col1a1(r/r) mice) have severe developmental defects resembling those observed in MMP2-null humans.
View Article and Find Full Text PDFJ Investig Dermatol Symp Proc
September 2006
Infiltration of leukocytes into tissue is a common feature of many physiological and pathological conditions. Histopathologically, the diversity of leukocytes that infiltrate a tissue associated with a pathophysiologic response cannot be appreciated and/or examined unless highly selective immunologic detection methods are utilized. Specific populations of infiltrating leukocytes into squamous tissues harboring pre-malignant and/or malignant keratinocytes have recently been demonstrated to play a functionally significant role in the pathogenesis of squamous carcinomas.
View Article and Find Full Text PDFThe main function of the mammalian immune system is to monitor tissue homeostasis, to protect against invading or infectious pathogens and to eliminate damaged cells. Therefore, it is surprising that cancer occurs with such a high frequency in humans. Recent insights that have been gained from clinical studies and experimental mouse models of carcinogenesis expand our understanding of the complex relationship between immune cells and developing tumours.
View Article and Find Full Text PDFCellular stressors such as UV irradiation, chemical irritants, or an immune system challenge in an otherwise healthy host induce the production and release of cytokines, such as tumor necrosis factor (TNF) alpha, which are powerful regulators of tissue homeostasis. TNFalpha, an important mediator of inflammation in the skin and mucosa, often represents the first physiological response to such noxious stimuli. TNFalpha not only acts systemically to promote inflammation, but also locally at the site of the stimulus to modulate cell growth and survival.
View Article and Find Full Text PDFThe p53 tumor suppressor is stabilized in cells expressing the human papillomavirus type 16 (HPV-16) E7 oncoprotein. In contrast, expression of the HPV-16 E6 protein inactivates p53 by targeting it for proteasomal degradation. Since p53 activation is associated with protein accumulation we investigated the biochemical mechanisms and biological consequences of p53 stabilization in HPV-16 E7-expressing cells.
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