A. Zimber

Abnormal Expression of Gastric Mucin in Human and Rat Aberrant Crypt Foci during Colon Carcinogenesis

Colorectal cancer is a major cause of death in Europe and the USA, and much effort is therefore devoted to improve its early detection. In this article, we report the abnormal expression of gastric mucin in aberrant crypt foci (ACF) that appear in the colon mucosae removed from colorectal cancer patients and rats treated with methyl-N′-nitro-N-nitroso-guanidine (MNNG). We performed the immunoperoxidase test using monoclonal antibodies raised against gastric M1 mucin encoded by the MUC5AC gene and against rat gastric mucins (MAb 660), respectively. In both human and rat colon, these anti-gastric mucin MAbs stained specifically goblet cells within ACF. In humans, the M1/MUC5AC mucin was expressed in the upper part of the glands in hyperplastic ACF and in the typical ACF. In addition, the anti-gastric mucin MAbs stained some rare, scattered, histologically normal glands in the human and rat colon mucosae. These glands may be regarded as precursors of ACF. The abnormal expression of the MUC5AC gene constitutes a novel change in addition to genetic modifications already observed in ACF, and supports our previous findings demonstrating the potential of this gastric mucin as an early marker of human and rat colon carcinogenesis.

Progression of tumors arising from large ACF is associated with the MUC5AC expression during rat colon MNNG carcinogenis

Aberrant crypt foci (ACF) are microscopic lesions which have been postulated to precede the development of adenomas, precursors of colon cancer. The gastric M1/MUC5AC mucin has also been described as an early marker of colon carcinogenesis in the human and in the rat. To study changes in mucin expression associated with the genesis of tumors, Wistar rats were treated by intrarectal instillations of MNNG, twice a week for 2 weeks, and were sacrificed 10 (n = 20), 14 (n = 20), 22 (n = 20), 30 (n = 10) and 66 (n = 16) weeks after the beginning of the treatment. In the treated rats, the MUC5AC mucin was mainly expressed in ACF compared with the histologically normal mucosae, which showed few isolated MUC5AC‐positive normal crypts. During carcinogenesis, the percentage of large ACF [≥≥10 aberrant crypts] increased and the number of MUC5AC‐positive (NCs) decreased. At Week 30, small tumors were observed arising from large ACF, both types of lesions expressing MUC5AC. At Week 66, large tumors showed remnants of MUC5AC‐positive ACF in their adjacent mucosae. This observation suggests that the expression of MUC5AC is associated with the ACF/adenoma sequence and supports the notion of large ACF as precursors of adenomas/adenocarcinomas. Moreover, the expression of MUC5AC in the transitional mucosa adjacent to both rat and human colon tumors suggests that some human tumors could arise from large ACF, and reinforces the concept of the premalignant potential of these lesions.

Isolation and characterization of a novel retrovirus from sheep affected by pulmonary carcinoma

Sheep pulmonary carcinoma (SPC) has been shown to be associated in nature with a retrovirus, by electron microscopic, biochemical, and epidemiological criteria and by experimental transmission. In this study, a retrovirus has been isolated from SPC tumors which were experimentally induced by inoculation with a cell-free, reverse transcriptase containing fraction from a spontaneous field case of SPC, and propagated in culture. This novel virus was shown to be unrelated to murine, avian, and bovine leukemia viruses, to be exogenous to the ovine species, and to have only limited genetic relatedness to the lentiviridae (maedi-visna and caprine arthritis encephalitis virus).

Lymphoproliferative disease of turkeys: Pathogenesis, Viraemia and serum protein analysis following infection 1

Turkey poults inoculated with plasma obtained from turkeys affected with lymphoproliferative disease (LPD) developed typical lymphoproliferative lesions in the pancreas, spleen and thymus, 3 and 6 weeks post infection. Virus-associated reverse transcriptase activity in plasma reached a significant level at 3 weeks and was further elevated at 6 weeks post infection, concomitantly with a marked increase in serum IgG, 7S-immuno-globulin level. There was no alteration in serum total iron binding capacity (transferrin) level in LPD virus-infected animals, as compared to controls. Natural field cases of LPD also demonstrated elevated serum IgG levels which persisted for more than 3 months, along with viraemia. There was a significant decrease in serum albumin concentration in about 30% of the infected animals, but in few of these turkeys was total serum protein elevated due to the very marked increase in gamma-globulins (IgG).

Susceptibility of domestic birds to Lymphoproliferative disease virus (LPDV) of Turkeys 1

The susceptibility of domestic ducks, geese and chickens to infection with lymphoproliferative disease virus (LPDV) of turkeys was tested. Infection with LPDV was assayed by measuring the particle-associated DNA polymerase in plasma. Ducks and geese were not susceptible to infection with this virus. Chickens were susceptible to the infection with LPDV and some of the birds developed a persistent viraemia. Six serial passages in chickens of viraemic plasma were achieved. Lymphoproliferative gross and microscopic lesions caused by LPDV infection were less frequent and less severe in chickens than in turkeys. LPDV infection in chickens was proven by the reproduction of LPD in turkeys by inoculation of chicken viraemic plasma, and by molecular hybridisation between LPDV (3H)cDNA and RNA extracted from the plasma and organs of inoculated chickens.

Comparative susceptibility of two turkey strains to lymphoproliferative disease virus.

The susceptibility to lymphoproliferative disease (LPD) of 1-day-old and 3-week-old poults of two turkey strains (A and B) was examined. Their susceptibility to infection with the causative virus was evaluated by the level and the duration of viraemia and by the presence of gross and microscopic lymphoproliferative lesions. Although in field conditions the incidence of outbreaks of LPD in strain A turkeys was much higher than in strain B, both lines were found to be of similar susceptibility to infection under experimental conditions.

The arotinoid Ro 40-8757 has antiproliferative effects in drug-resistant human colon and breast cancer cell lines in vitro

We have examined the antiproliferative effects of the arotinoid Ro 40-8757 in 3 drug-resistant human adenocarcinoma cell lines: the colonic cells HT29-5FU and CaCo2, and the mammary cells MCF-7mdr1. Whereas all-trans retinoic acid had no effect at the concentration of 10(-6) M, Ro 40-8757 was found to exert a high antiproliferative action with similar inhibitory potency (IC50) in drug-resistant and parental cell lines (range, 0.06 x 10(-6) to 0.57 x 10(-6) M). We conclude that: (1) thymidylate synthase is not involved in the mechanism of action of Ro 40-8757; (2) the mdr1 gene product does not recognize this retinoic derivative, and (3) Ro 40-8757, alone or in combinations with other cytotoxic drugs, can be very useful in patients with progressive disease after conventional chemotherapy.

Lymphoproliferative disease of turkeys: effect of chemical and surgical bursectomy on viraemia, pathogenesis and on the humoral immune response.

Turkey poults which were surgically or chemically bursectomised after hatching, and inoculated with the lymphoproliferative disease (LPD) virus at 3(1/2) weeks of age, developed typical tumourous lesions in various organs (pancreas, spleen, thymus, liver, gonads and kidneys) to the same extent as intact but inoculated controls. Plasma virus-associated reverse transcriptase activity (as an estimation of viraemia) developed at a higher rate in poults neonatally treated with 16 mg of cyclophosphamide. The chemically bursectomised birds were found to have markedly reduced serum gamma-globulins levels, and low levels or absence of agglutinins to sheep red blood cells and to killed Brucella abortus following immunisation with these antigens. Inoculation of turkey poults with LPD virus did not cause inhibition of the humoral immune response in intact birds but reduced significantly antibody production in surgically bursectomised poults. Since infection with LPD virus was previously shown to cause hypergammaglobulinaemia, and more specifically, a marked increase in serum IgG (7S) levels, it was suggested that the LPD tumour cells might be antibody-producing B-lymphoid cells. However, results presented here indicate that LPD lesions and viraemia can develop even in turkeys lacking any appreciable B-cell activity.