alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis

Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.     

Correlation and significance of histopathological and clinical features in breast cancer with skin involvement (T4b)

A retrospective review was performed to investigate the prognostic significance and validity of the pathological and clinical TNM staging of noninflammatory skin involvement in breast cancer. In 128 tumors with histologically proven skin involvement and a size up to 5 cm (64% of the entire group), we distinguished clearly between group A) cases showing the classical clinical signs (cT4b) and those that do not, and between group B) carcinomas infiltrating the epidermis (pT4b) and those infiltrating only the dermis. We found only moderate concordance (kappa = 0.44) between the pathological and clinical TNM staging system. In the analysis of 80 patients with a tumor size from 2.1 to 5.0 cm, neither the appearance of classical clinical signs nor the histological diagnosis of infiltration of the epidermis was shown to be a relevant factor. In comparison to the control groups, similar clinicopathologic entities without significant differences in long-term outcome were observed. After regrouping of the patients having tumor infiltration of the papillary dermis from the control group into the study group (pT4), the study group showed a significant higher number of involved axillary lymph nodes (P = .014) and a more extensive lymph node involvement (pN3; P = .025). The combination epidermis-papillary dermis seems to be more a functional unit than the epidermis alone that is defined as the crucial and delineating factor in the TNM Classification. Our results challenge the validity of the TNM rules and recommendations concerning T4b breast cancer because it leads, in the majority of cases, to tumors of comparable extent and prognosis being placed in different categories.     

“Lowe syndrome: A particularly severe phenotype without clinical kidney involvement”

Lowe syndrome (LS) is a very rare disorder of phosphatidylinositol metabolism, which manifests with a complex phenotype comprising a clinical triad encompassing major abnormalities of the eyes, the kidneys, and the central nervous system. We are reporting a 23‐year‐old Egyptian male with a severe phenotype of LS with a minimal kidney disease. Direct sequencing of the OCRL gene detected a p.His375Arg mutation in the catalytic domain of the protein. The patient suffered from bilateral congenital cataracts and glaucoma, striking growth deficiency, severe psychomotor disability, a severe osteopathy, and seizures, but only minimal renal dysfunction. Although the biological mechanisms underlying the pathophysiology of LS manifestations is yet unclear, it has been proposed that growth delay and osteopathy are linked to a renal dysfunction. This report, however, argues this association and suggests that kidney dysfunction may partially explain the growth deficiency and bone abnormalities, but other still undefined factors might have a potential impact.