Serge Jothy

Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule

Carcinoembryonic antigen (CEA) is a member of a family of cell surface glycoproteins that are produced in excess in essentially all human colon carcinomas and in a high proportion of carcinomas at many other sites. The function of this widely used tumor marker and its relevance to malignant transformation is therefore of considerable interest. We demonstrate here that CEA mediates Ca2+-independent, homotypic aggregation of cultured human colon adenocarcinoma cells (LS-180) and rodent cells transfected with functional CEA cDNA. Furthermore, CEA can effect the homotypic sorting of cells in heterogeneous populations of aggregating cells. CEA can thus be considered a new addition to the family of intercellular adhesion molecules. We also show that, whereas CEA is localized mainly to epithelial cell membranes facing the lumen in normal adult intestine, it is found on adjacent cell membranes in both embryonic intestine and colonic tumors. A model for the role of CEA in the tissue architecture of adult, embryonic, and aberrant tumor intestinal epithelium is presented.

Nef Harbors a Major Determinant of Pathogenicity for an AIDS-like Disease Induced by HIV-1 in Transgenic Mice

Transgenic (Tg) mice expressing the complete coding sequences of HIV-1 in CD4+ T cells and in cells of the macrophage/dendritic lineages develop severe AIDS-like pathologies: failure to thrive/weight loss, diarrhea, wasting, premature death, thymus atrophy, loss of CD4+ T cells, interstitial pneumonitis, and tubulo-interstitial nephritis. The generation of Tg mice expressing selected HIV-1 gene(s) revealed that nef harbors a major disease determinant. The latency and progression (fast/slow) of the disease were strongly correlated with the levels of Tg expression. Nef-expressing Tg thymocytes were activated and alpha-CD3 hyperresponsive with respect to tyrosine phosphorylation of several substrates, including LAT and MAPK. The similarity of this mouse model to human AIDS, particularly pediatric AIDS, suggests that Nef may play a critical role in human AIDS, independently of its role in virus replication.

Interleukin-6 and its receptor are expressed in human intestinal epithelial cells

SummaryRecent studies have suggested that intestinal epithelial cells demonstrate some of the functions associated with immune competent cells. Based on these observations, we investigated whether gastrointestinal epithelial cells express Interleukin-6 (IL-6). The presence of this cytokine was tested in 53 normal and pathological tissue specimens of the human gastrointestinal tract using an immunohistochemical technique with anti-IL-6 monoclonal and polyclonal antibodies. Immunostaining shows that IL-6 is expressed in gastric and small intestinal epithelial cells. The tumor cells from a large subset (11 of 15) of colon cancer specimens were strongly immunostained. IL-6 immunostaining was less conspicuous and less frequent in the epithelial cells of normal colonic mucosa. Northern blot experiments indicated that the expression of IL-6 in colonic mucosa correlates quantitatively with the presence of its m-RNA. Furthermore, IL-6 receptor (IL-6R) m-RNA was also detected and was twice as abundant in colonie carcinoma as in normal colon. It is concluded that mucosal epithelial cells of the gastrointestinal system express IL-6 and that in the case of the colon, malignancy is accompanied by a higher expression. In addition, the presence of IL-6R transcript suggests that normal and neoplastic colonie epithelial cells might be autocrinally regulated by IL-6.

CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein.

The CDKN2A gene encodes p16 (CDKN2A), a cell‐cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ‐line mutations in CDKN2A predispose to the familial atypical multiple‐mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1α and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis‐sense mutation resulting in a methionine to isoleucine change at codon 53 (M53I) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall‐bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M53I change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi‐site cancer families without melanoma are very unlikely to contain CDKN2A mutations. Int. J. Cancer 73:531–536, 1997.

Cardiac disease in transgenic mice expressing human immunodeficiency virus-1 nef in cells of the immune system.

We previously reported that a severe acquired immune deficiency syndrome-like disease develops in transgenic (Tg) mice expressing the human immunodeficiency virus-1 in its natural target cells: immature and mature CD4(+) T cells and cells of the macrophage/dendritic lineage. Here, we show that these mice also develop cardiac disease, characterized most prominently by a focal myocytolysis, occasionally by myocarditis and by deposition of endogenous immunoglobulin on cardiomyocytes. Microfil perfusion demonstrated widespread coronary arteriospasm and echocardiographic analysis revealed depressed cardiac function in Tg mice. A higher (but still modest) level of cardiomyocyte apoptosis was detected in Tg as compared to non-Tg hearts. Tg expression was detected in some of the infiltrating mononuclear cells, but not in cardiomyocytes or in cells of the heart vessels, suggesting a human immunodeficiency virus-1-induced disease process mediated by cells of the immune system. The similarity of the heart disease observed in these Tg mice to that observed in acquired immune deficiency syndrome patients suggests a common pathogenesis.

Field effect of human colon carcinoma on normal mucosa : Relevance of carcinoembryonic antigen expression

Human colon cancer usually develops on a mucosa which has already undergone multiple steps of genetic change. These multiple steps create a field effect characterized by the presence of morphologically normal, but biologically altered epithelial cells. This aims of this study were to evaluate whether the expression of carcinoembryonic antigen (CEA) can act as a phenotypic marker of the field effect, and to map its topography in relation to the presence of colorectal adenocarcinoma. The expression of CEA was tested by immunohistochemistry on morphologically normal mucosa at 4 increasing distances from 14 autologous cases of colorectal adenocarcinoma. CEA expression in the normal mucosa was compared to the tumor. The results show that in the mucosa adjacent to the edge of the autologous tumor, CEA is expressed to the same level as displayed in the carcinoma; there is a decrease in CEA expression in normal mucosa located at 1 cm or more from the edge of carcinoma. Mucosa sampled at 5 and 10 cm from the tumor expresses CEA at the same low level as in mucosa of control subjects with no colorectal neoplasm. In conclusion, this study demonstrates a gradient of CEA expression in the peritumoral area, supporting the concept of field effect, and maps its extent. These data are relevant to the biology of human colorectal cancer, and more practically, to the optimal location of surgical resection.

The levels and biologic action of the human neutrophil granule peptide HP-1 in lung tumors

HP-1 is the most abundant human representative of a recently discovered class of neutrophil cystine- and arginine-rich peptides. These peptides have many potentially regulatory activities expressed at nanomolar concentrations. To establish the levels of HP-1 that can accumulate in human lung tumors and nondiseased lung fragments, tissues were extracted for their peptide content. The extracts were purified on reverse phase HPLC, and HP-1 and related peptides were identified by sequence analysis and their concentrations in the tissue quantitated by amino acid analysis. Immunohistochemistry was performed and strongly suggests that HP-1 is confined to granulocytes under most circumstances, and indicates that the levels of HP-1 measured in the tumors reflect the levels obtained when solid tissue is infiltrated by neutrophils. The maximum observed levels were 26 nanomoles per gram wet weight of tissue. Attempts were then made to correlate this level to the cytotoxic potential of HP-1 by performing in vitro cytotoxicity dose-response curves on several cell lines. Most cells were killed at between 1 and 8 microM, and the response depended on the growth conditions of the cells. The levels of HP-1 that accumulate in tumors can exceed the in vitro cytolytic concentrations. The levels are also considerably in excess of those required to exert in vitro regulatory actions.

Adhesion or anti-adhesion in cancer: what matters more?

SummaryThe regulation of adhesion processes between normal epithelial cells is an essential condition for the maintenance of appropriate tissular architecture and differentiation. Quantitative and qualitative alterations in these homotypic adhesions occur during the transformation of normal into malignant epithelium. How these complex alterations in various homotypic adhesions modify the ability of tumor cells to detach from the original neoplastic site, to grow and move as single or clumped cells, and to invade the stroma are current issues in tumor biology. This review contrasts tumor cell adhesion mediated by E-cadherin which is consistently decreased in carcinomas, with adhesion mediated by CD44 and CEA which are increased in the same tumors. A model proposing to resolve the apparent paradox of simultaneous adhesion and anti-adhesion mediated by the same protein is proposed.

Anti–glomerular basement membrane glomerulonephritis after extracorporeal shock wave lithotripsy

Extracorporeal shock wave lithotripsy (ESWL) is a common noninvasive procedure for removal of upper urinary tract stones. We present a case of a man who developed anti-glomerular basement membrane (anti-GBM) disease after ESWL and review the two other cases described in the medical literature. In all cases, the affected individuals expressed the HLA DR2/HLA DR15 major histocompatibility antigen and developed a rapidly progressive anti-GBM-induced glomerulonephritis 3 to 7 months after ESWL. Anti-GBM disease may be a rare complication of ESWL in susceptible individuals and should be considered in patients who develop acute renal failure after lithotripsy.

D-Penicillamine-lnduced Crescentic Glomerulonephritis and Antimyeloperoxidase Antibodies in a Patient with Scleroderma

Therapeutic use of D-penicillamine has been associated with a range of adverse effects. We present a patient with scleroderma, treated with D-penicillamine for 5 years, who developed severe renal failure due to rapidly progressive glomerulonephritis with both crescents and subepithelial immune deposits on renal biopsy. Serological findings included perinuclear antineutrophil cytoplasmic antibodies and antihistone antibodies. She was treated with cyclophosphamide, prednisone, discontinuation of D-penicillamine, and hemodialysis. Therapy resulted in partial recovery of renal function. The clinical course of our patient is in keeping with D-penicillamine-induced chronic membranous nephropathy, followed by rapidly progressive crescentic glomerulonephritis. We discuss the effects of D-penicillamine in our patient, and review the literature on immune-mediated renal disease associated with the use of this drug.