The G 1 /S checkpoint of the cell cycle is regulated by p16, p53 and RB tumor suppressor genes. Loss of expression of the p16 INK4 tumor suppressor protein, the product of the CDKN2 gene, has been associated with a wide variety of human malignancies. Mutations, loss of heterozygosity and deletions of the CDKN2 locus have been reported in sporadic and familial cutaneous malignant melanomas (CMM). To investigate the role of the alterations of p16 expression in melanoma, we evaluated by immunohistochemistry the p16 expression and cell proliferation in 79 primary CMM and 10 benign melanocytic nevi (BMN). Forty-six melanomas (58%) and all BMN were found to be p16 positive; 33 melanomas (42%) were considered p16 negative. The extent of invasion according to Clark was significantly higher in p16-negative tumors than in p16-positive tumors. Cell proliferation as expressed by the proportion of positive cells in Ki-67 immunostaining was found to be significantly higher in p16-negative tumors than in p16-positive tumors, although there was no significant difference in the mitotic index between p16-positive and p16-negative tumors. In p16-positive tumors, the number of Ki-67-positive cells correlated with the mitotic index; in p16-negative tumors, there was no correlation between these parameters. Our data suggest that loss of p16 expression is more common in advanced melanomas, and that G 1 /S checkpoint regulation is disrupted in p16-negative melanomas. Our results show that loss of p16 expression is a common event in primary melanomas, which further substantiates the role of p16 as a major tumor suppressor. Int. J. Cancer 74:255-259, 1997.r 1997 Wiley-Liss, Inc.The progression of mammalian cells from the G 1 phase of the cell cycle to the S phase is regulated by a cascade of protein-protein interactions and protein phosphorylations. During G 1 , the D-type cyclins (cyclin D1, D2 and D3) accumulate and form complexes with CDK4 and CDK6. Cyclin D-CDK4/6 complexes phosphorylate the retinoblastoma protein (pRB), which is found in its hypophosphorylated form during G 1 . The phosphorylation of pRB releases a group of transcription factors essential for progression to S phase and onset of DNA replication. p16 INK4 , the protein product of the CDKN2 gene, is thought to be induced by some of these transcription factors to dissemble and inactivate the cyclin D-CDK4/6 complexes. p16 might also be induced earlier in G 1 by various anti-proliferative signals, arresting the cell in G 1 and thus acting as a powerful G 1 /S checkpoint regulator (reviewed by Grana and Reddy, 1995;Sherr and Roberts, 1995).The growth-inhibitory function of p16 makes it a candidate tumor suppressor. Loss of heterozygosity (LOH), homozygous deletion or mutations of the p16 gene have been found in cell lines established from malignant melanoma; mesothelioma; leukemia; glioma; carcinomas of lung, colon, liver, kidneys, esophagus, pancreas, breast, bladder, ovaries and prostate; and various sarcomas (Liu, Q. et al., 1995;Okamoto et al., 1994). Although it has ...

Decorin is a small extracellular chondroitin/dermatan sulfate proteoglycan that has previously been shown to be involved in the angiogenesis-like behavior of endothelial cells (ECs) in vitro. There is also evidence that decorin plays a role in angiogenesis in vivo. In this study we sought to further explore the involvement of decorin in angiogenesis in vivo, especially in that associated with inflammation. We found by CD31 immunostaining of ECs that in giant cell arteritis there are capillary blood vessels not only in the adventitia as in uninvolved temporal artery wall, but also in the media and the external zone of the thickened intima. Localization of decorin by antiserum LF-30 in adjacent sections showed that in normal temporal artery wall decorin resides mainly in the media and the adventitia, whereas in inflamed temporal artery wall decorin is distributed throughout the vessel wall including the intima. Furthermore, the most intense reaction for decorin was evident in ECs of capillary neovessels within the media and the thickened intima of inflamed temporal artery wall. Decorin was also found in capillary ECs in certain pathological and physiological conditions in which the pivotal role of angiogenesis is more generally accepted. Pyogenic granulomas, granulation tissue of healing dermal wounds, and ovaries at different phases of follicle and corpus luteum formation all contained widely distributed CD31-positive capillaries. Decorin, on the other hand, was found in capillary ECs in pyogenic granulomas and granulation tissue, but not in those in the ovaries. The assessment of the degree of inflammation in the specimens with the presence of CD68-positive macrophages showed that the pyogenic granuloma, granulation tissue, and giant cell arteritis specimens were rich in macrophages around the decorin-positive capillaries. In contrast, the ovarian specimens were populated with fewer macrophages and even they were not located in close vicinity of capillaries negative for decorin. Our results confirm that decorin is involved in angiogenesis in vivo and, particularly, in conditions in which the inflammatory component is dominant.

No abstract

An ulcerated tumour was removed by a Whipple's operation from the descending part of the duodenum of a 38-year-old male. The tumour cells were mainly spindle-shaped, arranged in nests and had very prominent nucleoli. A few cells contained melanin and melanosomes. Immunoreactivity for S-100 protein and focally for HMB-45 was observed. These features are diagnostic for clear cell sarcoma of tendons and aponeuroses. Because no other primary tumour could be found and the search for similar cases from the literature was unsuccessful, we believe that this tumour is the first reported clear cell sarcoma in a visceral location.

Intravascular malignant lymphomatosis (IML) is a highly malignant, recently recognized form of lymphoma. It is characterized by multifocal proliferation of malignant lymphocytes within small blood vessels, primarily in the central nervous system and skin, frequently resulting in circulatory disturbances. The cause of the impaired capability of the malignant lymphocytes to extravasate has remained unclear. We analyzed the presence of immunoreactivity for certain homing receptor and adhesion molecules associated with lymphocyte extravasation in 3 patients with this disease. Compared with non-neoplastic leukocytes, large malignant lymphocytes appeared either negative or only weakly positive for the leukocyte surface glycoprotein, CD18 that is the beta chain of the CDIIa/CD18 complex (lymphocyte-function associated antigen-I, LFA-I), which mediates cell-to-cell adhesion of lymphocytes. On the other hand, antibody to one of the proposed ligands for this complex, intercellular adhesion molecule-I, gave positive reactivity both on lymphocytes and on endothelial cells. Further, the malignant lymphoid cells stained positively with Hermes-3 antibody, which recognizes a common structure of CD44 class of molecules involved in lymphocyte homing. It was also shown that HECA-452 antigen, a marker of high endothelial venules (HEV) supporting lymphocyte extravasation, can be synthesized by an IML patient even at the site of inflammation but it is not prerequisite for extravasation of inflammatory lymphocytes. Our results suggest that the deficiency or absence of the adhesion molecule CDIIa/CD18 may contribute to the inability of the malignant lymphoid cells to extravasate in IML, and perhaps also to the high malignancy of this form of lymphoma.