The normal mammary microenvironment suppresses the tumorigenic phenotype of mouse mammary tumor virus-neu-transformed mammary tumor cells.

The microenvironment of the mammary gland has been shown to exert a deterministic control over cells from different normal organs during murine mammary gland regeneration in transplantation studies. When mouse mammary tumor virus (MMTV)-neu-induced tumor cells were mixed with normal mammary epithelial cells (MECs) in a dilution series and inoculated into epithelium-free mammary fat pads, they were redirected to non-carcinogenic cell fates by interaction with untransformed MECs during regenerative growth. In the presence of non-transformed MECs (50:1), tumor cells interacted with MECs to generate functional chimeric outgrowths. When injected alone, tumor cells invariably produced tumors. Here, the normal microenvironment redirects MMTV-neu-transformed tumorigenic cells to participate in the regeneration of a normal, functional mammary gland. In addition, the redirected tumor cells show the capacity to differentiate into normal mammary cell types, including luminal, myoepithelial and secretory. The results indicate that signals emanating from a normal mammary microenvironment, comprised of stromal, epithelial and host-mediated signals, combine to suppress the cancer phenotype during glandular regeneration. Clarification of these signals offers improved therapeutic possibilities for the control of mammary cancer growth.

Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-alpha.

Remodeling of the airways, as occurs in asthmatic patients, is associated with the continual presence of inflammatory mediators and Th2 cytokines, especially interleukin (IL)-13, during cycles of epithelial injury and repair. In this study, we examined the effect of IL-13 on well-differentiated normal human bronchial epithelial (NHBE) cells maintained in air-liquid interface culture. IL-13 induced proliferation of NHBE cells after 24 h exposure, as reflected by [(3)H]thymidine uptake and cell counts. The effects of IL-13 were mediated through the epidermal growth factor receptor (EGFR), as proliferation was attenuated by AG1478, an EGFR tyrosine kinase inhibitor. Proliferation appeared to be mediated by transforming growth factor (TGF)-alpha, a potent ligand for EGFR, which was released rapidly from NHBE cells in response to IL-13. Neutralizing antibody to TGF-alpha, but not antibodies against other potentially important growth factors (EGF, heparin binding epidermal growth factor-like growth factor [HB-EGF], platelet-derived growth factor [PDGF]), inhibited the mitogenic response to IL-13. This study provides the first experimental evidence that IL-13 can initiate a proliferative response of human airway epithelium in the absence of inflammatory cells or other cell types. The results are consistent with a mechanism whereby IL-13 induces release of TGF-alpha from the epithelial cells, which in turn binds via an autocrine/paracrine-type action to the EGFR, initiating proliferation. IL-13-induced airway remodeling in vivo may involve this epithelium-driven response.

Hypertrophic pulmonary osteoarthropathy and breast cancer.

Hypertrophic pulmonary osteoarthropathy is an uncommon, poorly understood syndrome usually seen with bronchogenic carcinomas, and rarely with tumors metastatic to the lungs or mediastinum. In a review of the literature, we have found only 140 cases associated with nonbronchogenic intrathoracic tumors. We have reported a case associated with metastatic breast carcinoma in which surgical resection led to rapid disappearance of the syndrome and prolonged palliation for the patient.

An epizootic of measles in captive silvered leaf-monkeys (Presbytis cristatus) in Malaysia.

An epizootic of measles occurred in a group of 31 silvered leaf-monkeys (Presbytis cristatus) that had been in captivity for 4-12 months. Twenty-four of the monkeys exhibited a maculopapular rash that persisted for 6-9 days. A serous to mucopurulent nasal discharge and conjunctivitis were seen in some animals. Eight monkeys died during the epizootic; however, their deaths could not be directly attributed to measles. Serum samples from the surviving monkeys collected 1-2 months prior to, and 5 weeks after, the epizootic were examined by the complement-fixation and hemagglutination-inhibition tests for antibodies to measles virus. The preepizootic complement-fixation titers were all less than 1:4 and hemagglutination-inhibition titers, less than 1:10. The postepizootic complement-fixation titers in 21 of 23 surviving monkeys ranged from 1:8 to 1:128, and hemagglutination-inhibition titers in 22 of 23 monkeys ranged from 1:40 to 1:80 or greater.

Enhancement of infectivity of encephalomyocarditis virus RNA by amphotericin B methyl ester.

The methyl ester of amphotericin B (AmBME), a macrolide polyene antibiotic, enhanced the infectivity of encephalomyocarditis (EMC) virus RNA for L929 cells. AmBME alone (100 microgram/ml) resulted in increases in EMC virus RNA infectivity of 10- to 100-fold. Addition of DEAE dextran at concentrations (5 microgram/ml), which alone slightly suppressed EMC virus RNA infectivity, further augmented the effects of AmBME (augmentation in infectivity up to 750-fold). AmBME did not inhibit RNase, did not enhance EMC virus infectivity and increased infectivity of EMC virus RNA which was already cell-associated. The polyenes are probably acting by increasing intracellular penetration of polyribonucleotides.

Increase by calcium in production of interferon by L929 cells induced with polyriboinosinate-polyribocytidylate complex.

Calcium chloride (5 to 20 mM) potentiated interferon production induced by rIn:rCn in L929 mouse fibroblasts up to a thousand-fold. Higher concentrations of calcium (20 to 65 mM) mixed with rIn:rCn were associated with increased cytotoxicity and a more acidic medium, but were effective in enhancing interferon production if preparations were adjusted to a uniform pH. Although calcium increased cellular binding of 3H-rCn:rIn, only a partial correlation between binding and interferon production was observed.

Mechanistic studies of polyene enhancement of interferon production by polyriboinosinic-polyribocytidylic acid.

The production of interferon by polyriboinosinic-polyribocytidylic acid [poly(I) . poly(C)] and poly(I) . poly(C)-diethylaminoethyl-dextran in L929 cells was enhanced from 10 to 100 times by polyene macrolides, including amphotericin B (AmB), AmB methyl ester, nystatin, and filipin. AmB and its water-soluble methyl ester were the most effective; retinol, a nonmacrolide polyene, was ineffective. Interferon induction by Newcastle disease virus was not enhanced by AmB. The kinetics of interferon production were not markedly altered by AmB. Polyenes and poly(I) . poly(C)-diethylaminoethyl-dextran did not need to be present on cells simultaneously to enhance interferon production. Pretreatment with polyenes was as effective as simultaneous addition. Even treatment of washed cells, several hours after removal of poly(I) . poly(C)-diethylaminoethyl-dextran, resulted in enhancement of interferon production. AmB did not appear to form a macromolecular complex with poly(I) . poly(C) in that neither the ultraviolet absorption spectrum nor the melting point of poly(I) . poly(C) was altered by mixing with AmB. Isotopic studies indicated that AmB did not enhance binding of poly(I) . poly(C) to cells. Since the macrolide polyenes have been demonstrated to bind to cell membrane sterols with subsequent alterations in membrane permeability barriers, they may enhance interferon production by increasing cell penetration of poly(I) . poly(C).