Hendrik Uyttendaele

Exposing the human nude phenotype.

The recent discovery of the human counterpart of the hairless mouse phenotype has helped our understanding of the molecular genetics of hair growth. But there are no reports of a defect in the human homologue of the best known of the ‘bald’ mouse phenotypes, the nude mouse. This may be because affected individuals are so gravely ill from the accompanying immunodeficiency that their baldness goes unnoticed. We have carried out a genetic analysis that reveals a human homologue of the nude mouse.

Expression of an activated Notch4(int-3) oncoprotein disrupts morphogenesis and induces an invasive phenotype in mammary epithelial cells in vitro

The protein encoded by the Notch4 gene is a member of the Notch/lin‐12 family of transmembrane receptor proteins, which have been shown to control cell fate determination and cell differentiation in a wide variety of organisms. Expression of Notch4(int‐3), a truncated form of Notch4 having most of its extracellular domain deleted, as a transgene in mice induces the formation of poorly differentiated mammary carcinomas. To establish whether Notch4(int‐3) has the capacity of subverting normal epithelial architecture, we assessed the effect of Notch4(int‐3) expression on the in vitro morphogenetic properties of TAC‐2 mammary epithelial cells. When grown in three‐dimensional collagen gels in the presence of hydrocortisone, both wild‐type and LacZ‐transfected TAC‐2 cells formed alveolar‐like structures composed of polarized epithelial cells surrounding a central lumen. In contrast, TAC‐2 cells programmed to express Notch4(int‐3) formed compact cell aggregates devoid of tissue‐specific organization. In addition, when grown on the surface of a collagen gel, Notch4(int‐3)‐expressing TAC‐2 cells invaded the underlying matrix, whereas TAC‐2 LacZ cells remained strictly confined to the gel surface. Expression of Notch4(int‐3) in TAC‐2 cells also disrupted contact‐inhibition of cell proliferation, resulting in cell multilayering. Our results suggest that the ability of Notch4(int‐3) to subvert normal epithelial morphogenesis and to promote invasion of the extracellular matrix contributes significantly to its tumorigenic potential. Int. J. Cancer 86:652–659, 2000.

Drugs and nails

In this issue, Ghetti et al . report on the occurrence of onycholysis and subungual haemorrhages after paclitaxel therapy. This report adds to the ever-increasing list of cancer chemotherapeutic agents that are associated with certain nail abnormalities. Obviously, it is important for clinicians to recognize specific drug-induced side-effects. However, these reports may also provide us with molecular agents that can be used to analyse and dissect the homeostatic mechanisms that control the nail unit. Drug-induced nail abnormalities are characterized by the frequent involvement of all 20 nails, a temporal correlation with drug intake, and the usual disappearance upon cessation of the offending drug. 1 Toenails may seem to be less affected, but this is probably due to the slower growth rates of these nails. Most commonly, the drug has a direct toxic effect on one of the components of the nail apparatus. Depending on which nail component(s) (nail matrix, bed, folds, plate (secondary to matrix involvement) or hyponychium) is affected, a variety of nail changes may be observed. 2 For instance, drug toxicity to nail matrix keratinocytes may result in Beau’s lines, onychomadesis, leuconychia, nail plate abnormalities such as brittle and thin nails, and decreased or increased nail growth rates. By contrast, drug toxicity to nail bed keratinocytes may result in onycholysis and pseudo-leuconychia. Nail abnormalities can also depend on the cell type that is affected. Many of the drug-induced nail pigmentation changes are the result of increased melanin production by nail matrix melanocytes. On occasion, the nail abnormalities are secondary to drug-induced toxicities outside the nail unit. For instance, splinter haemorrhages and subungual haematoma can be caused by vascular damage or impaired perfusion of the nail bed. Cancer chemotherapeutic agents often induce nail changes, and nail pigmentation is probably the most frequently observed nail abnormality. 3 The mechanism of drug-induced hyperpigmentation is not fully understood, but this is most probably due to increased melanogenesis in matrix melanocytes. Different patterns of hyperpigmentation such as longitudinal bands, transverse bands and diffuse darkening have been described after the administration of many different cancer chemotherapeutic drugs. Beau’s lines, transverse leuconychia and onychomedesis are the result of nail matrix toxicity, and can be seen after intensive or combined chemotherapy. Nail bed toxicity, as manifested in apparent leuconychia or onycholysis, may be seen in association with nail bed haemorrhage, which may be exacerbated by concurrent thrombocytopaenia. Acute paronychia has also been described after treatment with methotrexate. 4