The insulin-like growth factor axis and prostate cancer: lessons from the transgenic adenocarcinoma of mouse prostate (TRAMP) model.

We have characterized the temporal expression of the insulin-like growth factor (IGF) axis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model as prostate cancer progression in this model closely mimics that observed in the human disease, and the model provides samples representing the earliest stages of prostate cancer that are clinically the most difficult to obtain. We report that prostate-specific IGF-I mRNA expression increased during prostate cancer progression in TRAMP mice and was elevated in the accompanying metastatic lesions, whereas prostatic IGF-I mRNA remained at nontransgenic levels in androgen-independent disease. Expression of IGF-II mRNA, however, was reduced in primary prostate cancer, metastatic lesions, and androgen-independent disease. Expression of type-1 IGF receptor (IGF1R) mRNA, encoding the cognate receptor for both IGF-I and IGF-II, as well as type-2 IGF receptor (IGF2R) mRNA was not found to be altered during primary prostate cancer progression in intact TRAMP mice but was dramatically reduced in metastatic lesions and in androgen-independent disease. Similar to reports from clinical disease, serum IGF-I levels were observed to increase precociously in TRAMP mice early in disease progression but remained at nontransgenic levels after castration. Elevated serum levels of IGF-binding protein 2 were observed to correlate with advanced prostate cancer in the TRAMP model. Together these observations implicate IGF-I as an important factor during the initiation and progression of primary prostate cancer and provide evidence that there is a strong selection against expression of IGF1R and IGF2R in metastatic and androgen-independent disease.

Characterization of the FGF axis and identification of a novel FGFR1iiic isoform during prostate cancer progression in the TRAMP model.

Expression of the fibroblast growth factor (FGF) axis was examined during prostate cancer progression in the autochthonous Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model, including TRAMP derived cell lines. Transcripts for FGF-7 and FGF-10 that are normally expressed by the stroma were detected in all samples, including the epithelial cell lines, suggesting that elaboration of these factors by the epithelium may be an essential event during transformation. Interestingly FGFR2iiib, the FGF-7 and FGF-10 receptor, was downregulated during tumor progression whereas a novel FGFR1iiic (Phi) inframe splice form was found to be expressed. These observations support the hypothesis that specific changes in FGF axis correlate with, and probably facilitate, tumor progression.

Peptide growth factors and prostate cancer: new models, new opportunities.

Prostate cancer is the leading form of newly diagnosed cancer cases in men in the United States. However, the molecular mechanisms contributing to the initiation, progression and ultimate development of metastatic and androgen independent disease are poorly understood. This is due in part to the difficulty in obtaining clinical samples representing early disease and the lack of animal models that recapitulate the full spectrum of the clinical disease. To this end we have developed and characterized the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal model that expresses the oncogene SV40 T antigen specifically in the epithelium of the prostate. TRAMP develops spontaneous autochthonous prostate cancer compelte with distant site metastasis and can progress to androgen independent disease. Changes in the fibroblast growth factor (FGF) axis and the insulin-like growth factor (IGF) axis have been examined during prostate cancer progression utilizing the TRAMP model and these data generally support observations reproted in the clinical disease. Moreover, we report novel changes in the FGF axis and IGF axis utilizing TRAMP. Thus, TRAMP can be used as a potent tool in understanding the mechanism of prostate cancer initiation and progression.

Algaemia due to Prototheca wickerhamii in a patient with myasthenia gravis.

Prototheca wickerhamii is a rare cause of systemic infection in humans. While some cases occur in previously healthy individuals, others are associated with a variety of preexisting diseases. Here we present, for the first time, a case of P. wickerhamii algaemia in a patient with myasthenia gravis. The patient was successfully treated with amphotericin B.

Involvement of transforming growth factor alpha (TGFalpha) and epidermal growth factor receptor (EGFR) in sex hormone-induced prostatic dysplasia and the growth of an androgen-independent transplantable carcinoma of the prostate.

We previously reported the induction of dysplasia, a putative precursor of carcinoma, in the dorsolateral prostates (DLPs) of Noble rats by the combined administration of testosterone (T) and estradiol-17beta (E2) for 16 weeks. Additionally, we demonstrated growth of the AIT, a DLP-derived, androgen-independent, transplantable solid tumor, in castrated syngeneic hosts. In this investigation, using Northern blot hybridization, radioimmunoassays and radioligand assays, we showed that transforming growth factor-alpha (TGFalpha) and epidermal growth factor receptor (EGFR) were expressed at close to non-detectable levels in the ventral prostates but at low, but measurable, levels in the DLPs of untreated rats. Enhanced expression of this ligand and its receptor was detected in the DLPs harboring dysplasia and marked overexpression of these molecules was noted in the AIT. In contrast, epidermal growth factor (EGF) expression was found to be constitutively expressed, at high levels, in both normal and dysplastic DLPs, but virtually absent in the AIT. Immunohistochemical data suggested that EGF, TGFalpha and EGFR were aprocine secretory products of the normal DLP, with TGFalpha and EGF localized to the supranuclear complexes and EGFR to the apical membranes of epithelial cells. Alterations in immunostaining patterns for TGFalpha and EGFR were exclusively detected in the dysplastic lesions in the DLPs of T + E2-treated rats. Enhanced intracytoplasmic localization for both peptides were found to accompany the loss of cell polarity in dysplastic foci. Strong intracytoplasmic immunostaining for TGFalpha was observed in some AIT cells whilst staining for EGFR was present in the membranes of tumor cells that formed psuedoacini. Taken together, our findings suggest that autocrine mechanisms may play an important role early in the carcinogenic process and that progression to an androgen-independent neoplastic growth may be modulated by this signaling pathway.

Mycoplasma neurolyticum membranes: a T-independent antigen in the rat.

Our understanding of the mechanisms involved in B cell activation, proliferation and differentiation to immunoglobulin secreting cells has been facilitated by the use of T-independent and T-dependent antigens. The majority of these studies have used the murine system and only recently, the rat. Because membranes isolated from Mycoplasma neurolyticum are potent B cell mitogens in the rat and some T-independent antigens also activate DNA synthesis in B cells, the in vitro and in vivo antibody responses induced by M. neurolyticum membranes in T-deficient rat systems were examined. The three groups of rats used, i.e., nude; anti-thymocyte serum-treated, neonatally-thymectomized (ATS-Tx); and normal Fischer 344 produced a non-polyclonal antibody response against the membranes. Spleen cell cultures that were T cell deficient and B cell enriched produced plaque-forming cells against the Mycoplasma membranes. Antibody production was depleted upon removal of Sephadex G-10 adherent cells. The antibody response is comprised of both antigen-specific and polyclonal responses. Lipoglycan, found in the aqueous phenol extract of the membranes, is the mitogenic fraction of the membranes, and this study suggests that it may also be the T-independent antigenic component of the M. neurolyticum membranes.

Affective empathy and cognitive role-taking in delinquent and nondelinquent youth.

Ten male and 10 female delinquents were compared with 10 male and 10 female nondelinquents on a structured self-reported affective empathy task, an unstructured affective empathy task, and a cognitive role-taking measure. Differences between groups were found only on the unstructured empathy task, with delinquents performing more poorly than nondelinquents. Sex differences were noted in the delinquent sample on the structured empathy task, with males demonstrating less empathic responding than females. The role of empathic skills in the etiology of delinquent behavior is addressed. In addition, the need to further differentiate the cognitive and affective components of the empathic construct is emphasized.

Age-related changes in responsiveness of various rat tissue lymphocytes to mitogens.

The effect of age on the mitogen responses of rat lymphoid tissues was investigated. Evaluation was based on using the in vitro proliferative response of lymphocytes from various tissues of Fischer-344 rats (2, 7, 13, 19 and 25 months) using concanavalin A (Con A), phytohemagglutinin-P (PHA-P), pokeweed mitogen (PWM) and Mycoplasma neurolyticum. The stimulation index (S.I.) for cervical, mesenteric, thymic and splenic lymphocytes treated with Con A and PHA-P was greatest for 2-month-old rats and lowest for 19-month-old rats; however, no age-related change was observed with either PWM or M. neurolyticum. The levels of mitogenic responses for lymph nodes in the two different anatomical sites paralleled one another, with the cervical lymphocytes showing a greater response. The splenic lymphocytes responded less than either lymph node lymphocyte population. When PHA-P treatment of splenic lymphocytes followed the removal of the plastic adherent population, the S. I. of the resulting non-adherent population was comparable to the S. I. of other tissue lymphocytes; however, an age-related decrease was still observed. The PHA-P proliferative response of either the 7- or 19-month non-adherent population was suppressed by the 7-month adherent population and not by the 19-month adherent population i.e., adherent population interaction with non-adherent population decreases with age.

Bovine serum albumin humoral immune response in aged Fischer 344 rats.

The circulating antibody titers to bovine serum albumin (BSA) were determined for two groups of aged Fischer 344 rats obtained form the National Institute on Aging. One group received a single immunization of BSA in complete Freund's adjuvant, and the second group was immunized three times at two-week intervals with twice the antigen dosage. An age difference was observed during the peak response in both groups, the younger rats having higher titers; however, upon multiple injections the older rats show an enhanced response although significantly lower than the younger rats. All antibody titers increased at the same rate, yet measurable antibody always appeared first in younger animals.