transforming-growth-factor-alpha and Lymphoma

Transforming growth factor alpha (TGFalpha) is a potent inducer of cellular transformation, through its binding and activation of the epidermal growth factor receptor (EGFR). Previous studies in our laboratory showed that EGFR could also be affected by the glycoprotein MUC1, which inhibits ligand-stimulated degradation of EGFR in breast epithelial cell lines. To determine the effect of Muc1 expression on TGFalpha/EGFR-dependent breast transformation, we crossed the WAP-TGFalpha transgenic mouse model of breast cancer onto a Muc1-null background. We found that the loss of Muc1 expression dramatically affects mammary gland transformation and progression. Although 100% of WAP-TGFalpha/Muc1(+/+) mice form mammary gland tumors by 1 year, only 37% of WAP-TGFalpha/Muc1(-/-) form tumors by this time. This difference is also associated with a delay in onset, with a doubling of onset time observed in the WAP-TGFalpha/Muc1(-/-) compared with the WAP-TGFalpha/Muc1(+/+) mice. Analysis of signal transduction pathways revealed that activation of cyclin D1 expression is significantly suppressed in tumors derived from WAP-TGFalpha/Muc1(-/-) animals compared with those expressing Muc1. The loss of Muc1 expression also results in a significant inhibition in the formation of hyperplastic lesions during tumor progression. On the C57Bl/6 inbred background, pulmonary lesions were observed in 28 of 29 WAP-TGFalpha/Muc1(+/+) animals (including one metastatic pulmonary adenocarcinoma and multiple perivascular lymphomas), although none were detected in the WAP-TGFalpha/Muc1(-/-) animals. Together, these data indicate that Muc1 is an important modulator of TGFalpha-dependent tumor progression.

Topics: Animals; Disease Models, Animal; Disease Progression; Gene Expression Regulation, Neoplastic; Lymphoma; Mammary Neoplasms, Animal; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Mucin-1; Neoplasm Metastasis; Signal Transduction; Time Factors; Transforming Growth Factor alpha

We have previously reported the antimetastatic effect of a single low-dose of cyclophosphamide (Cy) on L-TACB rat lymphoma. The phenomenon could be adoptively transferred in immunocompetent rats and is abolished in nude mice, facts for which an immunomodulatory explanation was proposed. The aim of this paper was to identify the mechanism(s) by which spleen cells from Cy-treated tumour-bearing rats could exert this antimetastatic activity. Conditioned media obtained by incubation of spleen cells from Cy-treated and non-treated tumour-bearing rats, under specific or non-specific stimulation, were assayed to evaluate their effect on lymphocyte proliferation. The production of transforming growth factor beta (TGF-beta), interleukin-10 (IL-10) and nitric oxide (NO) by conditioned media was also studied. The restoration of spleen lymphoproliferative responses to normal levels when exposed to media conditioned by splenocytes from Cy-treated tumour-bearing rats, together with a decreased production of suppressive cytokines TGF-beta, IL-10 and NO, suggest an enhancement of host antimetastatic immunity triggered by single low-dose Cy treatment.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Division; Cyclophosphamide; Female; Immunosuppressive Agents; Interleukin-10; Lymphoma; Male; Neoplasm Metastasis; Nitrites; Rats; Transforming Growth Factor alpha

To determine the role of a specific member of the metalloproteinase family, stromelysin-1, in mammary carcinogenesis and tumor progression, transgenic mice expressing activated rat stromelysin-1 under the control of the mouse mammary tumor virus promoter/enhancer were treated with the carcinogen 7,12-dimethylbenzanthracene (DMBA) to induce mammary tumors. Surprisingly, the expression of stromelysin-1 during the time of DMBA treatment reduced the number of mice developing mammary tumors, in particular adenoacanthomas, from 65 to 32% (P = 0.02). In contrast, when transgenic mice expressing both transforming growth factor alpha and stromelysin-1 under the control of the mouse mammary tumor virus long terminal repeat were treated with DMBA, there was no significant difference in the number of mice that developed tumors compared to transforming growth factor alpha controls. A 4-fold increase in the number of apoptotic cells was detected in stromelysin-1 transgenic mice compared to littermate controls at the time of DMBA administration, suggesting that the reduction in DMBA-induced tumorigenicity is likely to be due, at least in part, to an increased rate of cell turnover in stromelysin-1 transgenic mice. When malignant adenocarcinomas developed in the stromelysin-expressing mice, there was no detectable alteration in the extent of invasion or in the metastatic potential of these tumors compared to tumors from control mice. These results suggest that the expression of a single metalloproteinase, stromelysin-1, is insufficient for the progression of mammary adenocarcinomas to an invasive and metastatic phenotype, but that matrix degradation by metalloproteinases can alter basic processes of cell proliferation and apoptosis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Adenoma; Animals; Animals, Suckling; Apoptosis; Cell Division; Female; Lung Neoplasms; Lymphoma; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 3; Metalloendopeptidases; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Neoplasm Invasiveness; Neoplasm Proteins; Time Factors; Transforming Growth Factor alpha