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P M Heidger

Publications and source records attributed to P M Heidger.

At least 19 recordsLinked to original sources
PubMed2001

Molecular determinants of ovarian cancer plasticity.

During development, the formation and remodeling of primary vascular networks occurs by vasculogenesis and angiogenesis. Recently, the term "vasculogenic mimicry" has been used by our laboratory and collaborators to reflect the embryonic-like ability of aggressive, but not nonaggressive, melanoma tumor cells to form a pattern of matrix-rich networks (containing channels) surrounding spheroids of tumor cells in three-dimensional culture, concomitant with their expression of vascular cell markers. Ovarian cancer is usually diagnosed as advanced stage disease in most patients when widespread metastases have already been established within the peritoneal cavity. In this study, we explored whether invasive ovarian carcinoma cells could engage in molecular vasculogenic mimicry reflected by their plasticity, compared with their normal cell counterparts. The data revealed that the invasive ovarian cancer cells, but not normal ovarian surface epithelial cells, formed patterned networks containing solid and hollow matrix channels when grown in three-dimensional cultures containing Matrigel or type I collagen, in the absence of endothelial cells or fibroblasts. Immunohistochemical analysis showed that matrix metalloproteinases (MMP)-1, -2, and -9, and MT1-MMP were discretely localized to these networks, and the formation of the networks was inhibited by treatment with MMP inhibitors. Furthermore, the RNase protection assay revealed the expression of multiple vascular cell-associated markers by the invasive ovarian cancer cells. In patient tumor sections from high-stage, high-grade ovarian cancers, 7 to 10% of channels containing red blood cells were lined by tumor cells. By comparison, all vascular areas in benign tumors and low-stage cancers were endothelial lined. These results may offer new insights and molecular markers for consideration in ovarian cancer diagnosis and treatment strategies based on molecular vascular mimicry by aggressive tumor cells.

Female↗
PubMed1999

A novel immunological model for the study of prostate cancer.

The Dunning R-3327 rat prostatic adenocarcinoma is a widely accepted model for in vivo experimental studies of prostate cancer. We have previously derived phenotypically distinct cell lines from a s.c. tumor resulting from the inoculation of the R-3327-5 subclone into Copenhagen rats. In this study, we report studies using a gelatin sponge model for the delivery of tumor cells and the retrieval of tumor-specific leukocytes responsive to different prostatic cell lines. S.c. preimplanted sponges were inoculated with tumor cells previously selected for differential properties of tumor formation and metastasis and examined for leukocyte content at time points of 1, 3, and 5 weeks after tumor cell inoculation. Cytospin and flow cytometric analyses revealed fewer tumor-associated leukocytes present in sponges inoculated with tumorigenic R-3327-5' and R-3327-5'B lines, with lesser sponge degradation, than in experiments with the nontumorigenic R-3327-5'A line, suggestive of a tumor cell-induced immunomodulatory mechanism. Morphological studies indicate an intermittent tumor growth pattern that gradually disappears in sponges inoculated with the nontumorigenic R-3327-5'A cells but a robust growth pattern in sponges inoculated with the tumorigenic cell lines. Cytokine analyses show the secretion of higher levels of active transforming growth factor-beta by the more invasive and metastatic lines. Total transforming growth factor-beta levels are higher in the epithelial, tumorigenic R-3327-5'B line. Additionally, the more tumorigenic lines secrete interleukin 10, a potent immunosuppressive molecule. In this report, we demonstrate the ability to retrieve viable leukocyte populations from a prostate tumor line bearing sponges, which offers an important model for further in vitro and in vivo manipulations and holds promise for testing adoptive immunotherapeutic strategies.

Adenocarcinoma↗
PubMed1997

Fine structural studies of induced tumors arising within the prostatic complex of Lobund-Wistar rats.

BACKGROUND: Morris Pollard, Phyllis Luckert, and colleagues have reported the occurrence of spontaneously arising tumors of the prostatic complex in aged Lobund-Wistar (L-W) rats, and have also shown that the genesis of such tumors may be accelerated by means of intravenous administration of methylnitrosourea, followed by androgen supplementation. METHODS: Light and electron microscopic investigations of the tumors arising under this regime were conducted, with the objective of documenting morphological changes attending the transformation process; 10 tumor samples were used for the electron microscopic studies. RESULTS: All tumors studied were adenocarcinomas arising within the prostatic complex of induced animals. These tumors varied in size, degree of differentiation, and invasiveness. Foci of prostatic intraepithelial neoplasia were noted in light microscopic studies as well. Consistent fine structural features exhibited by cells of the induced adenocarcinomas included a large nuclear to cytoplasmic ratio; large irregular nuclei with heavily marginated chromatin; conspicuous nucleoli; abundant ribosomes and polysomes and a paucity of rough endoplasmic reticulum; and numerous cytoplasmic vesicles and lipid inclusions. Numerous, short microvilli extended from the cell surface into a copious surrounding extracellular matrix. CONCLUSIONS: Thus, these tumors shared many of the fine structural features characteristic of the Dunning (rat) and human prostatic adenocarcinomas.

Adenocarcinoma↗
PubMed1994

Gross and microscopic pathology of induced prostatic complex tumors arising in Lobund-Wistar rats.

The necessity for additional animal models for prostate cancer has recently been stressed. The Pollard model of chemically induced prostate cancer has received attention in this regard although the histiogenetic origin of these tumors has come under question. We independently studied this model for the development of tumors in the prostate region. The tumors, all of which were adenocarcinomas, first became grossly evident 5 months after induction and ultimately occurred in 71% of the animals. Seventy-three % of the tumors involved only the seminal vesicle, 22% involved other portions of the prostatic complex as well as the seminal vesicle, and 5% were located in the coagulating gland (anterior prostate). Although the majority of tumors arose in or involved the seminal vesicle, this may still be a useful model for the study of human prostate cancer because the tumors are adenocarcinomas, occur in the large majority of animals, are hormonally induced, and have the propensity to metastasize.

Adenocarcinoma↗
PubMed1993

Cell wall deficient bacteria as a cause of idiopathic hematuria.

Idiopathic hematuria in the absence of bacteriuria is a medical challenge. Routine cultures of catheterized bladder and endoscopically obtained ureteral urine specimens from a 22-year-old woman with a 6-week history of hematuria showed no growth after 24 to 48 hours of incubation. However, bacterial variants were grown on enriched media. Colonies were typical cell wall deficient/defective bacteria. Phase and electron microscopy of cystoscopic urine specimens obtained by retrograde ureteral catheterization as well as phase microscopy of the cultures revealed the classic morphology of these organisms. When the variant cultures were subcultured the organisms reverted to their related walled forms, that is Streptococcus agalactiae and Staphylococcus haemolyticus. Because the colonies of these organisms showed various patterns of biochemical reactivity, each phenotype was tested against 15 antimicrobials. Collectively, all biotypes had a common susceptibility to only nitrofurantoin. The patient was treated with nitrofurantoin for 6 weeks. Four days after initiation of therapy she had complete remission of hematuria. During the next 3 years she remained well and free of hematuria.

Adult↗
PubMed1993

Peptidergic nerves in the ureter.

Vasoactive intestinal peptide (VIP) and substance P were demonstrated in the pig ureter by immunohistochemical techniques. Nerves containing these materials were related mainly to the smooth muscle layer in the normal and obstructed ureter. In isolated ureteral segments, VIP caused relaxation at doses exceeding 0.18 micrograms/ml, with no significant difference seen in the effect on normal and obstructed ureter. Vasoactive intestinal polypeptide may play a role in the regulation of ureteral smooth muscle tone.

Animals↗
PubMed1992

Human doubled renal and testicular arteries.

Doubled renal and testicular arteries were found in a well-developed 69-year-old caucasian male. The right kidney had two renal arteries, one at its usual midorgan (hilar) position and one inferior polar. One testicular artery arose from the mid-point of the usual renal artery, passed under the renal vein at its junction with the inferior vena cava, and then crossed over the inferior polar renal artery. The second testicular artery arose from the inferior polar renal artery near its origin from the abdominal aorta. The two testicular arteries remained doubled throughout their course and both entered the right testis at separate sites on the organ. The inferior vena cava passed under the inferior polar and over the superior testicular artery and the superior renal artery.

Aged↗
PubMed1986

Immunocytochemical localization of metallothionein in the rat prostate gland.

Metallothionein (MT), which binds zinc and other metals, was localized within the rat prostatic complex at light and electron microscopic levels utilizing immunocytochemistry. Two groups of mature, male Sprague-Dawley rats were injected with cadmium chloride subcutaneously (2 mg/kg body weight) to induce the synthesis of MT, and were sacrificed 48 h postinjection. From the first group, prostatic tissue from the three lobes was prepared for light microscopy. The indirect peroxidase antiperoxidase procedure was used for MT localization using rabbit anti-MT as the primary antibody. The three lobes of the rat prostate demonstrated a positive reaction for MT, but among the lobes variations in the intensity and localization of the reaction product occurred. Tissues from the second group of animals were prepared for electron microscopy. Using the indirect immunogold labeling technique with anti-MT, MT localization was confirmed in the rough endoplasmic reticulum, secretory vesicles, secretory products, and subepithelial connective tissue. These localizations suggest that MT binds zinc both intra- and extracellularly, where it may function in zinc storage and metabolism.

Animals↗
PubMed1986

Stereological study of Leydig cell density in the guinea pig testis.

Stereological analysis of Leydig cell and macrophage volume density along the long axis of the guinea pig testis was assessed quantitatively by histometric point counting. Morphological identification of Leydig cells was accomplished by staining for 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), whereas macrophages were identified by vital staining (trypan blue). The average percentage of Leydig cell density constitutes about 10.17 +/- 0.23% at the cranial level (level 1) and about 8.8 +/- 0.21% at the caudal level (level 4). Leydig cell density through four testicular levels showed no significant difference among levels 1, 2, and 3, whereas level 4 was significantly different. The percentage of macrophage density, on the other hand, was approximately 0.4% +/- SEM per cross-sectional profile. It may thus be concluded that the macrophage density within the guinea pig testis does not bias histometric studies of the Leydig cell population to any significant degree, but that regional differences in Leydig cell volume density could influence validity of sampling if tissue procurement is from different testicular levels in successive experiments.

Animals↗
PubMed1985

Characterization of the heterogeneity of R3327 rat prostatic tumors derived from single-cell clones.

Prostatic adenocarcinoma is characterized by cellular diversity, which is well demonstrated in the Dunning R3327 rat prostatic adenocarcinoma. This heterogeneity may arise from epigenetic influences, ie, cellular adaptation or selection, and/or from genetic changes. To investigate the question of genetic instability, four tissue culture cell lines were derived from single cells isolated from the uncloned late (UCL) passage of the Dunning R3327H prostate cell culture. Each of these clonally derived tissue cultures was injected into castrated and intact young adult male rats for tumor production. Uncloned early (UCE) and UCL passage tissue cultures were also propagated as solid tumors. Tumors and the cultures from which they were derived were examined for evidence of phenotypic and genetic changes using morphological and cytometric methods. Transmission and scanning electron microscopy revealed only slight differences among the cell cultures. A single population of diploid cells was demonstrated in each of the cell cultures by propidium iodide staining and subsequent flow cytometric measurement of DNA content/nucleus. Tumors of unicellular as well as multicellular origin exhibited extreme heterogeneity of histological features, both among animals as well as within a single tumor. Tumors were surveyed and tissue types were characterized and cataloged. Clone 3 was generally better differentiated than the others; tumors from castrated animals were better differentiated than those from intact animals. Flow cytometry revealed multiple hyperdiploid cell populations that were variable from one sample to another. We concluded that changes in genotype as well as phenotype occurred in the tumors derived from single cells. Some of these changes may have occurred in the cells while still in culture.

Adenocarcinoma↗
PubMed1984

Androgen receptor binding characteristics in the cytosol of the rat dorsolateral prostate gland and the Dunning R-3327 prostatic adenocarcinoma.

The incidence of prostatic cancer is highly correlated with advanced age, and it has been suggested that changes in androgen binding may be important in age-associated alterations in growth regulatory mechanisms of prostatic epithelial cells. In this study the effects of age on androgen binding characteristics in the dorsolateral prostate glands of young and aged Copenhagen rats were determined and the binding properties in the Dunning R3327/130 subline of rat prostatic adenocarcinoma were characterized. Tritium-labeled and nonlabeled methyltrienolone analogs (R1881) were used to study the binding properties of 5 alpha-dihydrotestosterone receptor in the cytosol of tumors and prostate glands. Binding of R1881 was low but specific for the androgen receptor as shown by competition studies in which nonlabeled R1881, 5 alpha-dihydrotestosterone, and testosterone competed successfully with 3H-R1881 for binding sites, but 17 beta-estradiol and low levels of progesterone did not. In Copenhagen dorsolateral prostate, Scatchard analysis suggested a single class of binding sites. In young animals (three to five months) the average binding capacity was 10.36 fmol/mg cytosol protein with a dissociation constant (Kd) of 2.28 nmol/L. The dorsolateral prostate of aged rats (11-16 months) showed no significant difference in specific binding characteristics as compared to the younger age group. Specific binding of 3H-R1881 in R3327/130 tumor was saturable with a single class of high-affinity binding sites having an average binding capacity of 64.77 fmol/mg cytosol protein and a Kd of 2.76 nmol/L. These data show that the tumor had approximately 6.5 times the number of binding sites as did the normal Copenhagen rat dorsolateral prostate gland. However, no age-related changes were detected through 11-16 months of age in the androgen binding characteristics of normal rat dorsolateral prostate gland that could be correlated with the higher concentration of androgen binding sites in the R3327/130 tumor subline.

Adenocarcinoma↗
PubMed1984

Hormonal effects on zinc concentration and morphology of rat lateral prostate gland.

Hypophysectomized rats were injected with prolactin and/or testosterone, and luteinizing hormone (LH) and prolactin and/or follicle-stimulating hormone (FSH). Tissue from the lateral prostate was processed for spectrophotometric determination of zinc and for electron microscopy. Changes in zinc concentration, epithelial height, and morphological characteristics were used to assess the effect of hormonal replacement on functional activity. Although testosterone administration resulted in full restoration of all parameters, there was no evidence of a synergistic effect of prolactin and testosterone. Prolactin alone decreased the zinc concentration and increased the epithelial height compared with control animals, and there was evidence of epithelial hyperplasia. Luteinizing hormone, alone or combined with prolactin or prolactin and FSH, resulted in a marked increase of epithelial height and restoration of morphological features found in intact animals; however, only a slight increase of zinc concentration over control values was elicited. Combined LH and FSH administration reduced epithelial height and zinc concentration compared with the other LH regimes, and there was evidence of cellular degeneration.

Animals↗
PubMed1983

Electron microscopic and histochemical characterization of intra-arterial cushions of the rat and porcine uterine vascular bed.

Scanning and transmission electron microscopic studies, together with histochemical investigations, were conducted on rat and porcine intra-arterial cushions from the uterine vascular bed. In the rat, the fine structure of these cushions closely resembled that previously described in the rat kidney. The cushions were composed of modified smooth muscle, circularly disposed in an incomplete, raised band surrounding the entrance to arterial branches. These muscle cells projected as attenuated processes throughout the loosely organized, PAS-positive stroma, and established close contact with thin endothelial extensions projecting from the base of the surface endothelial cells. Scanning electron microscopic observations of furrows on the endothelial surface gave rise to the suggestion that such contacts might mediate muscular control of endothelial surface topology. In similar cushions from the pig uterine artery, the smooth muscle of the cushions was much more compactly organized, and was disposed radially, rather than circumferentially, within the cushion structure. The enzyme histochemical profile of porcine cushions did not differ appreciably from that of normal vascular smooth muscle and endothelium, suggesting the maintenance of a metabolic similarity with adjacent tissues. These studies clarify the fine-structural basis for recently reported contraction and relaxation of uterine artery cushions during ischemia and perfusion of the rat uterine vascular bed, and thus, for their functional role in the regulation of uterine vascular flow.

Animals↗
PubMed1980

Isolation, in vitro cultivation, and electron microscopy of normal and malignant prostatic epithelial cells from the Copenhagen rat.

Procedures are described for the isolation and cultivation of normal rat prostatic epithelial cells. The techniques, which involve collagenase digestion and Ficoll purification of the epithelial population, are efficient, inexpensive, and produce pure monolayers. Included is a scanning and transmission electron microscopic study comparing cells isolated in vitro to rat prostatic epithelial cells in situ. Further ultrastructural comparisons are made to a malignant cell line, the Dunning R3327H Copenhagen rat prostatic adenocarcinoma.

Animals↗
PubMed1979

Fine structural studies of rat seminal vesicle in castrated and intact animals following estrogen treatment.

The effect of estradiol and/or testosterone upon secretion by seminal vesicle in castrated and intact rats was assessed in young adult Sprague-Dawley rats, using light microscopy (LM), transmission (TEM) and scanning (SEM)electron microscopy. Hormones were injected daily for ten days beginning ten days after castrations were performed. The normal rat seminal vesicle, as revealed by SEM, was characterized by a large saccular lumen with highly folded walls. Cell surfaces were covered with microvilli, or occasionally displayed a protruding, ruffled surface, sparsely covered with short microvilli. Cytology was normal in testosterone-treated animals. Estradiol treatment of castrated animals stimulated secretion by seminal vesicle epithelial cells as evidenced by the presence of normal secretory bodies, the presence of RER, and moderately hypertrophied Golgi complexes. These glands were not heavier than were glands from castrated, untreated animals, although the epithelial cells were significantly taller. Secretion was maintained in intact animals treated with estradiol, although glands were smaller and epithelial height was reduced. Estradiol and testosterone treatment in combination did not appear to have an additive effect on secretion, weight of the gland, or epithelial height. The following results support the hypothesis that estrogen-induced prolactin synthesis and release may be involved in the mechanism by which estradiol effected stimulation of seminal vesicle epithelium. Prolactin-treated, castrated animals exhibited focal areas of stimulated epithelium. In hypophysectomized animals (untreated controls), the seminal vesicle epithelium retained some secretory bodies and secretory fluid in the glandular lumen; epithelial height was taller than that in castrated controls. Estrogen treatment reduced the epithelial height to that of castrated controls; there was no evidence of secretion. This suggests that in the absence of anterior pituitary hormones, including prolactin, the stimulatory effect of estradiol on seminal vesicle epithelium was nullified. In adrenalectomized/castrated animals, estradiol treatment stimulated secretion in seminal vesicle epithelium just as in non-adrenalectomized/castrated animals. This indicates that the adrenal gland plays a non-essential role in the action of estrogen on seminal vesicle epithelium.

Adrenal Cortex Hormones↗
PubMed1979

Fine structural studies of the rat vas deferens.

A fine structural study of the normal rat vas deferens was undertaken utilizing perfusion fixation. Morphological features not previously appreciated were revealed using this technique of fixation, and included the following. The rat vas deferens exhibited a gross morphological and microscopic differentiation along its length: A proximal segment was characterized by a thin muscular wall, an epithelium of low height (comparable to that of the cauda epididymidis) and a distended lumen typically filled with an accumulation of sperm; a distal segment exhibited a thick muscular wall, a convoluted mucosa, and a pseudostratified columnar epithelium with long stereocilia extending into the lumen. The transition from the morphology typical of the proximal segment to that of the distal segment was gradual and progressive, marked by an increase in the mass of the muscular wall and in the height and ultrastructural complexity of the epithelium. Clear or "foamy" cells, characteristic of the cauda epididymidis, were observed in the initial centimeter of the vas deferens. Also, a cell type designated as "mitochondrion-rich" was observed in the distal vas segment. The structure of the small mitochondria in such cells, however, did not conform to the description of mitochondria in similar cells found in the human (Hoffer, '76). Intraepithelial macrophages containing residual accumulations which often resembled spermatozoan remnants in advanced stages of dissolution were present in all segments of the rat vas deferens, confirming in this species a spermiophagic role for such cells.

Animals↗