PubMed Health⌕ Search

Biomedical subjects

G Merlino

Publications and source records attributed to G Merlino.

At least 73 records · Page 4Linked to original sources
PubMed1995

Central obesity and hypertension: pathophysiologic role of renal haemodynamics and function.

OBJECTIVE: To investigate the role of alterations in renal haemodynamics and function and in plasma renin activity on obesity-induced hypertension. DESIGN: Renal haemodynamics and function, salt-regulating hormones and structural cardiac parameters were evaluated in 20 lean normotensives and in 64 obese subjects with central or peripheral fat distribution, 43 of them were normotensives and 21 of them were hypertensives. Obesity and central fat distribution were defined according to sex-specific 85th percentile respectively of Body Mass Index (BMI) and Waist to Hip Ratio (WHR). MEASUREMENTS: Serum immunoreactive insulin (IRI), plasma renin activity (PRA), plasma aldosterone (PA), microalbuminuria (UAE) and 24h urinary excretion of sodium (NaU) were evaluated by current methods. Renal haemodynamics was evaluated by radionuclide study according to Schlegel's and Gate's methods. By radionuclide study, effective renal plasma flow (ERPF), effective renal blood flow (ERBF), glomerular filtration rate (GFR), filtration fraction (FF) and renal vascular resistances (RVR) were measured. Left ventricular mass (LVM) and indexed for body height (LVM/H), cardiac output (CO) and total peripheral resistances (TPR) by ecocardiography were also calculated. RESULTS: CO, LVM and LVM/H were significantly (P < 0.05) higher in all the obese groups than lean controls. In addition, LVM and LVM/H were significantly (P < 0.05) higher in obese hypertensives than obese normotensives either with central fat distribution. TPR values were significantly (P < 0.05) higher in central obese hypertensives than peripheral obese hypertensives and than central obese normotensives. Moreover, IRI levels were significantly (P < 0.05) higher in central normotensive and hypertensive obese subjects than lean subjects. ERBF and ERPF were significantly (P < 0.05) lower and PRA levels were significantly higher only in central obese than lean subjects. On the contrary RVR were significantly (P < 0.05) higher in both obese hypertensive groups and in central obese normotensives than lean subjects. Comparisons between peripheral and central obese groups indicated that PRA, RVR and UAE were significantly (P < 0.05) higher and ERBF and ERPF values were significantly (P < 0.05) lower in both central obese groups than comparable subjects with peripheral obesity. Multiple regression analysis indicated that RVR increased significantly (P < 0.05) with WHR and PRA but not with CO and IRI. CONCLUSIONS: Our results indicate that obesity with body fat distribution of central type, more than obesity of peripheral type, is associated to abnormalities in renal haemodynamics and function. These data are consistent with the indication that change in renal haemodynamics take place at an early stage in the obesity-induced hypertension.

Adult↗
PubMed1995

Transforming growth factor-alpha promotes mammary tumorigenesis through selective survival and growth of secretory epithelial cells.

Transforming growth factor (TGF)-alpha stimulates the growth and development of mammary epithelial cells and is implicated in the pathogenesis of human breast cancer. In this report we evaluate the consequences of overexpressing TGF-alpha in the mammary gland of transgenic mice and examine associated cellular mechanisms. When operating on a FVB/N genetic background (line MT100), TGF-alpha induced the stochastic development of mammary adenomas and adenocarcinomas f secretory epithelial origin in 64% of multiparous females. In contrast, tumors were exceedingly rare in virgin MT100 females, MT100 males, and multiparous FVB/N females. In MT100 females multiple foci of hyperplastic secretory lesions preceded the development of frank tumors; these initial lesions appeared during the involution period after the first lactation. Serial transplantation of these hyperplasias indicated an absence of proliferative immortality. Nevertheless, they gave rise to tumors at a low frequency and after a prolonged latency in virgin hosts; in multiparous hosts, tumors developed earlier and at a high incidence. The TGF-alpha transgene was highly expressed in hyperplasias and tumors but not in virgin and nonlesion-bearing tissue, suggesting that TGF-alpha overexpression provides a selective growth advantage. TGF-alpha also induced at lactation a 6.4-fold increase in DNA synthesis in MT100 epithelial cells, many of which were binucleated. MT100 mammary tissue experienced an obvious delay in involution, resulting in the postlactational survival of a significant population of unregressed secretory epithelial cells. In contrast, another line of transgenic mice on a CD-1 genetic background (MT42), in which TGF-alpha overexpression induced liver but not mammary tumors, failed to demonstrate postlactational epithelial cell survival. These data show that TGF-alpha promotes mammary tumorigenesis in multiparous MT100 mice by stimulating secretory epithelial cell proliferation during lactation and prolonging survival during involution. These points support the notion that TGF-alpha can act as a mitogen and also as a differentiation factor in mammary epithelium.

Adenocarcinoma↗
PubMed1995

Synergistic interaction of transforming growth factor alpha and c-myc in mouse mammary and salivary gland tumorigenesis.

The c-myc oncogene is commonly amplified in breast cancer and is known to interact synergistically with transforming growth factor alpha (TGF alpha) in vitro to promote phenotypic transformation of mammary epithelial cells. In addition, both genes are under sex steroid hormone regulation in breast cancer. We have used a bitransgenic mouse approach to test the relevance of Myc-TGF alpha interaction in mammary gland tumorigenesis of virgin animals in vivo. We mated single transgenic TGF alpha and c-myc mouse strains to yield double transgenic offspring for TGF alpha and c-myc. All (20 of 20) double transgenic TGF alpha/c-myc animals developed synchronous mammary tumors at a mean age of 66 days. An unexpected finding was that tumor latency and frequency in males and virgin females were identical. Thus, two gene products that are known to be coinduced in breast cancer by the sex hormones estrogen and progesterone strongly synergize to induce synchronous mammary tumors, independent of sex. The tumors, despite being estrogen receptor positive, were readily transplanted as highly malignant s.c. cancers in ovariectomized nude mice. Although approximately one-half of single transgenic c-myc virgin females also eventually developed mammary gland tumors, these were stochastic and arose after a long latency period of 9-12 months. Single transgenic virgin TGF alpha females and males, c-myc males, and transgene-negative littermates did not develop tumors (ages up to 15 months). The salivary glands of double transgenic animals also coexpress the two transgenes and show pathological abnormalities ranging from hyperplasias to frank adenocarcinomas. In contrast, the salivary glands of single transgenic and wild-type animals showed only mild hyperplasias or metaplasias, but tumors were not observed. In situ hybridization analysis of mammary and salivary glands revealed that hyperplastic and tumorous areas colocalize with regions that overexpress both the TGF alpha and c-myc transgenes. This indicates that there is a requirement for the presence of both proteins for transformation of these glands. In summary, TGF alpha and c-Myc synergize in an extremely powerful way to cause breast and salivary gland tumorigenesis in males and virgin females without a requirement for pregnancies.

Adenocarcinoma↗
PubMed1995

Hepatocarcinogenesis in transgenic mice.

Transgenic mouse models of altered hepatic gene expression have provided a new set of tools with which to study the molecular genesis of normal and pathological liver growth. Previously identified carcinogenic genomic changes (such as oncogene activation) can be tested for their transforming potency in liver, and the contribution to liver growth of genetic changes of unknown significance (such as expression of a growth factor) can be directly measured in vivo. Highly novel approaches also have become possible because of the liver's unique regenerative capacity following injury: introduction of cells from another mouse's liver into young AL-uPA mice has resulted in reconstitution of up to 80% of recipient liver by donor cells (Rhim et al., 1994). Use of immunotolerant mice and human donor cells in this approach should allow creation of mice carrying human livers. Finally, by combining transgenic and embryonic stem cell technologies, the latter allowing selective mutation or inactivation of desired genes, we now have the means to begin to answer many of the critical questions regarding mechanisms of liver growth regulation in the intact animal.

Albumins↗
PubMed1994

Autonomous growth in serum-free medium and production of hepatocellular carcinomas by differentiated hepatocyte lines that overexpress transforming growth factor alpha 1.

Transforming growth factor alpha (TGF-alpha) is a polypeptide closely associated with hepatocyte proliferation in vivo and in vitro. In order to investigate the mechanisms by which TGF-alpha contributes to hepatocyte replication and transformation, we isolated hepatocytes from mice bearing a human TGF-alpha transgene and examined their growth properties and gene expression in defined, serum-free culture. The transgenic hepatocytes continued to overexpress human TGF-alpha mRNA and peptide, and were able to proliferate without exogenous growth factors in primary culture, in contrast to nontransgenic mouse hepatocytes. In short-term culture the transgenic hepatocytes underwent 1 wave of DNA replication at 72-96 h in culture before senescing, similar to nontransgenic hepatocytes supplemented with epidermal growth factor. Constitutive expression of TGF-alpha rendered the transgenic hepatocytes unresponsive to further growth stimulation by exogenous TGF-alpha, as well as other mitogens such as epidermal growth factor and hepatocyte growth factor. However, it did not alter their sensitivity to growth inhibition by TGF beta 1, 2 and 3. The addition of nicotinamide to the culture medium enabled both transgenic and epidermal growth factor-supplemented normal hepatocytes to replicate repeatedly and survive for > or = 2 months in primary culture while maintaining differentiated traits. From these long-term primary cultures of transgenic and nontransgenic hepatocytes, we established immortalized cell lines (designated TAMH and NMH lines, respectively). Both lines continued to express differentiated adult hepatocytic markers such as albumin, alpha-1-antitrypsin, transferrin, and connexin 26 and 32 mRNAs, but also expressed mRNAs for the oncofetal markers alpha-fetoprotein and insulin-like growth factor II. Unlike the near-diploid NMH hepatocyte line, the transgenic TAMH hepatocyte line was quasi-tetraploid, strongly expressed human TGF-alpha mRNA, and was highly tumorigenic in nude mice. Well-differentiated hepatocellular carcinomas developed in nude mice given injections of the TAMH line, and these appeared similar to the primary liver tumors seen in TGF-alpha transgenic mice with regard to histology and strong expression of mouse and human TGF-alpha, insulin-like growth factor II, and alpha-fetoprotein mRNAs. Our data show that TGF-alpha overexpression causes autonomous hepatocyte proliferation and contributes to neoplasia but that additional cellular alterations must occur for carcinogenesis. Inappropriate expression of insulin-like growth factor II may constitute one of these steps. The TGF-alpha transgenic mouse hepatocyte line TAMH appears to undergo transformation in a similar manner to that of hepatocytes overexpressing TGF-alpha in vivo, and should serve as an ideal system in which to study hepatocarcinogenesis.

Animals↗
PubMed1994

Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha.

Hepatocytes are extensively used in studies of gene regulation but cannot be maintained in long-term culture as replicating, differentiated cells while remaining nontumorigenic. We have derived two hepatocyte lines from livers of transgenic mice overexpressing transforming growth factor alpha, a potent hepatocyte mitogen, which overcome these limitations. The transgenic hepatocytes were maintained for > or = 2 months in serum-supplemented primary culture and gave rise to cell lines, of which two (AML12 and AML14) have been cultured for > 1.5 years (> 80 passages). Both lines have typical hepatocyte features such as peroxisomes and bile canalicular-like structures, do not grow in soft agar, and are nontumorigenic in nude mice. Like normal hepatocytes, AML cells express high levels of mRNA for serum (albumin, alpha 1-antitrypsin, and transferrin) and gap junction (connexins 26 and 32) proteins, secrete albumin, and contain solely isozyme 5 of lactate dehydrogenase. After extensive passaging, AML12 cells continue to strongly coexpress hepatocyte connexin mRNAs but do not display nonparenchymal cell markers. Although mRNA levels for some serum proteins progressively fall, high expression in late AML12 cultures may be regained by passage in serum-free medium. The AML14 line loses expression of both differentiated markers and transgene mRNA with extended passaging, and hepatocytic traits are only partially restored by passage in serum-free medium. These differentiated, nontumorigenic cell lines should serve as models in which to study hepatocyte growth and differentiation.

Animals↗
PubMed1994

Central obesity and hypertension. Relationship between fasting serum insulin, plasma renin activity, and diastolic blood pressure in young obese subjects.

This study was designed to evaluate the role of fasting serum insulin and plasma renin activity in obesity-induced hypertension. In view of this, plasma catecholamines, fasting serum insulin (IRI), urinary sodium excretion (NaU), plasma renin activity (PRA), and plasma aldosterone (PA) levels were assessed in young (age less than 40 years) normotensive (n = 27) and hypertensive (n = 14) subjects with central obesity and in lean normotensives (n = 20). Central obesity was evaluated by waist-to-hip ratio (WHR) according to the indication of the Italian Consensus Conference of Obesity. PRA, PA, IRI, and plasma norepinephrine levels were significantly (P < .05) higher in both obese groups than in lean normotensives. PRA was significantly (P < .05) higher and NaU was significantly (P < .05) lower in obese hypertensives than in obese normotensives. Diastolic blood pressure correlated directly with WHR and PRA in normotensive and hypertensive obese subjects and with IRI but only in normotensive obese subjects. Multiple regression analysis indicated that diastolic blood pressure values increased with WHR (P < .05), IRI (P < .005), and PRA (P < .002), but not with body mass index, NaU, and norepinephrine levels. Our results indicated that increased PRA could play an important role in the development of hypertension in subjects with central obesity.

Adult↗
PubMed1994

Lymphocyte beta-adrenergic receptors in young subjects with peripheral or central obesity: relationship with central haemodynamics and left ventricular function.

This study was designed to evaluate total (t) and surface (s) beta-adrenergic receptor (BAR) density and their relationship with central haemodynamics and left ventricular function in young subjects with central or peripheral obesity. A total of 31 obese subjects (BMI > or = 30.5 kg.m-2 for males and > or = 27.3 kg.m-2 for females) aged less than 40 years and without other risk factors for cardiovascular diseases (smoking, hypertension, diabetes and lipid abnormalities) were studied. Nine had peripheral obesity and 22 central obesity according to WHR values; there were 20 lean controls (BMI < 25 kg.m-2 for males and < 24.7 kg.m-2 for females). Casual (c) and 24 h ambulatory mean blood pressures (MBP-24 h) were determined. BAR density was evaluated according to Böyum and De Blasi methods. Plasma catecholamines by high perfusion liquid chromatography and fasting immunoreactive plasma insulin (IRI) were also measured by RIA. Radionuclide angiocardiography was used to determine central haemodynamics and both systolic and diastolic left ventricular function. Total peripheral resistances (TPR) and intravascular volumes were also determined. Echocardiographic study was used to measure LVM, LVM.h-1, LVDD and IVS. Left ventricular ejection fraction (LVEF), peak filling rate (PFR), BARt and BARs were significantly lower (P < 0.05) and cardiac output, cardiac volumes, LVM, LVM. h-1 and time to PFR significantly higher (P < 0.05) in both obese groups than in lean controls. Plasma IRI was significantly (P < 0.05) higher in both obese groups whereas plasma norepinephrine was higher only in central obese.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Overexpression of a human transforming growth factor-alpha (TGF alpha) transgene reveals a dual antagonistic role of TGF alpha in female sexual development.

The importance of transforming growth factor-alpha (TGF alpha) in female reproductive development was assessed using transgenic mice bearing a human TGF alpha complementary DNA under the control of a mouse metallothionein-1 promoter (MT1-hTGF alpha). Examination of the brain and ovaries 5 h after a single sc injection of zinc chloride, administered to activate the MT1-hTGF alpha transgene, revealed that prominent sites of human TGF alpha messenger RNA expression within these tissues were the hypothalamus and ovarian follicles, respectively. In vitro experiments showed that acute transgene activation increased hypothalamic release of LH-releasing hormone. In contrast, the ovarian steroidal response to gonadotropins, examined in vitro, was markedly attenuated. Chronic activation of transgene expression by daily administration of zinc chloride delayed the time of first estrus (an index of peripubertal estrogen secretion), but shortened the interval between first estrus and the onset of estrous cyclicity (an index of reproductive competence). Accumulation of small antral follicles, accompanied by thecal hypertrophy and enhanced androgen production, preceded the acquisition of ovulatory capacity. These changes were accompanied by reduced serum LH levels, suggesting that the relative inability of small antral follicles to develop further in TGF alpha-overexpressing mice is at least in part due to inappropriate gonadotropin support. Serum LH levels in these animals may be reduced by an augmented androgen negative feedback signal. Nontransgenic mouse ovaries, placed under the control of a transgenic hypothalamus by heterologous grafting, rapidly ovulated and initiated estrous cyclicity. In contrast, acquisition of reproductive capacity was severely delayed in nontransgenic mice bearing transgenic ovarian grafts. The results indicate that TGF alpha regulates female reproductive development through two opposing mechanisms: within the brain, it facilitates the neuroendocrine activation of the process; at the ovarian level, modulates the stimulatory effect of gonadotropin hormones on follicular growth and steroidogenesis.

Animals↗
PubMed1994

Association between reduced lymphocyte beta-adrenergic receptors and left ventricular dysfunction in young obese subjects.

This study was designed to evaluate total (t) and surface (s) beta-adrenergic receptors (BAR) density and their relationships with left ventricular function in young obese subjects. BAR density, plasma insulin, catecholamines and left ventricular function were evaluated in 27 young obese subjects (BMI > 30.5 kg/m2 for males and > 27.3 kg/m2 for females) without other risk factors for cardiovascular diseases (smoking, hypertension, diabetes and lipid abnormalities) and in 20 lean controls (BMI < 25 kg/m2 for males and < 24.7 kg/m2 for females). Both groups were matched for gender, age and body height. BAR density was evaluated according to Böyum and De Blasi methods. Plasma catecholamines by high perfusion liquid chromatography and fasting immunoreactive plasma insulin (IRI) levels by RIA were also measured. Casual (c) and 24 h ambulatory mean blood pressure (MBP/24h) were determined. Radionuclide angiocardiography was used to measure left ventricular ejection fraction (LVEF), peak filling rate (PFR), time to PFR (tPFR), cardiac output (CO) and stroke volume (SV). Total left ventricular mass (LVM), indexed for height (LVM/H), left ventricular diastolic dimension (LVDD) and interventricular septal (IVS) thickness by echocardio-graphic study were calculated. LVEF, PFR, BARt, BARs were significantly lower (P < 0.0001) and plasma IRI, CO, SV (P < 0.0001), LVM (P < 0.003), LVM/H (P < 0.004), LVDD (P < 0.02) and tPFR (P < 0.02) were significantly higher in obese subjects than in lean controls. BARt and BARs correlated inversely with BMI, SV and LVDD.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Transgenic mice provide genetic evidence that transforming growth factor alpha promotes skin tumorigenesis via H-ras-dependent and H-ras-independent pathways.

The epidermal growth factor receptor (EGFR), which mediates the mitogenic activity of transforming growth factor alpha (TGF-alpha), has been shown to activate Ras in cultured cells through well-defined intermediary proteins. To examine the in vivo relationship between EGFR and Ras, chemical carcinogenesis of TGF-alpha transgenic mouse skin was chosen as an experimental model. Transgenic mice overexpressing TGF-alpha in a wide variety of epithelial tissues by virtue of a metallothionein promoter demonstrate a multitude of premalignant and neoplastic lesions but not spontaneous skin tumors. Transgenic skin was initiated with a single dose of 7,12-dimethylbenz[a]anthracene (DMBA), shown previously to induce, in concert with a tumor promoter, murine papillomas that consistently contain specific H-ras mutations. Virtually all DMBA-treated TGF-alpha transgenic mice, but not treated control animals, developed hyperplasias, papillomas, sebaceous adenomas, and more infrequently, sebaceous and squamous cell carcinomas. Therefore, TGF-alpha functions as an autonomous tumor promoter in DMBA-initiated transgenic skin. Skin tumors could be separated into two mutually exclusive genetic classes. In tumors harboring mutant H-ras, TGF-alpha transgene expression was relatively low and essentially unchanged relative to untreated skin; however, only 42% of skin tumors contained mutations in H-ras. Conversely, in most tumors with wild-type H-ras, transgenic TGF-alpha transcripts were enhanced 10- to 20-fold. These results suggest that strong constitutive EGFR stimulation, through TGF-alpha transgene overexpression, can substitute functionally for mutational activation of H-ras in skin tumorigenesis. Moreover, because H-ras mutational activation could not induce skin tumors without TGF-alpha transgene activity, simultaneous stimulation of an EGFR-mediated H-Ras-independent pathway appears to be required for tumor development as well.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1994

Overexpression of transforming growth factor-alpha causes liver enlargement and increased hepatocyte proliferation in transgenic mice.

Transforming growth factor-alpha (TGF-alpha) expression is associated with hepatocyte DNA replication both in vivo and in culture. Our previous work using TGF-alpha transgenic mice showed that constitutive overexpression of this growth factor in the liver causes hepatic tumors in 75 to 80% of the animals at 12 to 15 months of age. To understand the cellular events by which TGF-alpha overexpression leads to abnormal liver growth, we examined hepatocyte proliferative activity in young and old TGF-alpha transgenic mice and hepatocyte ploidy in normal, dysplastic, and neoplastic livers of these animals. At 4 weeks of age, transgenic mice had higher liver weights and liver weight/body weight ratios than non-transgenic mice of the same age and hepatocyte proliferative activity, measured by 3H-thymidine incorporation after 3- and 7-day infusion, proliferating cell nuclear antigen staining, and mitotic index determination, was 2 to 3 times higher than in controls. In both transgenic and non-transgenic mice hepatocyte proliferation declined with age but the decrease was much more pronounced in control animals, so that at 8 months of age, hepatocyte replication was 8 to 10 times higher in transgenic animals. Surprisingly, however, transgenic and non-transgenic mice at this age had similar liver weight/body weight ratios. Labeling studies done in 3-month-old animals revealed that hepatocyte turnover was much faster in transgenic than in control animals, suggesting that a homeostatic compensatory mechanism involving cell death tended to restore normal liver weight/body weight ratios in older transgenic mice. Ploidy analyses showed that at 4 weeks of age transgenic mice had a higher proportion of diploid and tetraploid hepatocytes and that the hepatocellular tumors which developed in TGF-alpha transgenic mice at 13 months of age contained a higher fraction of diploid hepatocytes than that present in adjacent tissue or in dysplastic livers. The results demonstrate that constitutive overexpression of TGF-alpha causes increased hepatocyte proliferation and liver enlargement in young animals and is associated with a delay in the establishment of hepatic polyploidy. These findings as well as the response of transgenic mice to partial hepatectomy show that constitutive overexpression of TGF-alpha initially caused increased but regulated hepatocyte proliferation which in older animals was compensated in part by a faster cell turnover. At 8 to 10 months of age, proliferative activity may become constitutive in some TGF-alpha expressing hepatocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1994

Renal cysts in transgenic mice expressing transforming growth factor-alpha.

Transforming growth factor-alpha (TGF-alpha) is a member of the epidermal growth factor (EGF) family of proteins and, like EGF, elicits its cellular function by binding to the EGF receptor. EGF stimulation may have a role in several normal and pathologic processes in the kidney, and EGF has been implicated in the development of renal cysts in vitro and in human autosomal dominant polycystic kidney disease. We sought to determine whether renal expression of an EGF-like protein (TGF-alpha) could lead to the formation of renal cysts in vivo. We examined morphologic alterations to the normal kidney caused by renal expression of a TGF-alpha transgene linked to a mouse metallothionein promoter stably integrated into the genome of the CD1 mouse. TGF-alpha transgene expression was induced with exogenous zinc treatment starting at 4 weeks of age, and mice were killed at 8 weeks of age. The transgene was expressed at higher levels in female transgenic mice than in male transgenic mice. The augmented expression of the TGF-alpha transgene in females was associated with increased renal size and the development of renal epithelial cysts. Both male and female mice exhibited increases in glomerular size and mesangial volume density. These results provide evidence that stimulation by an endogenous EGF-like protein can lead to renal enlargement, glomerular mesangial expansion, and renal cyst formation.

Animals↗
PubMed1994

Regulatory imbalances in cell proliferation and cell death during oncogenesis in transgenic mice.

Whether a cell decides to proliferate, undergo growth arrest, or even commit suicide is determined by a multitude of highly potent positive and negative regulatory factors. Mutational perturbation of these factors and the normal pathways through which they regulate either cell proliferation or cell death can induce a pathologic enhancement in cell number, or hyperplasia, and eventually the development of malignant tumors. Serving as valuable animal models for cancer in humans, transgenic mice have been used to demonstrate the dramatic consequences of subverting the normal molecular mechanisms regulating cell proliferation and/or cell death. This review will use three transgenic mouse models to illustrate the consequences of inducing such regulatory imbalances, as well as the utility and versatility of the transgenic approach in cancer research. Three different regulatory factors are considered; transforming growth factor-alpha is discussed as an example of a positive growth regulator, p53 as a negative growth regulator, and Bcl-2 as an inhibitor of programmed cell death.

Animals↗
PubMed1993

Collaboration between growth factors and diverse chemical carcinogens in hepatocarcinogenesis of transforming growth factor alpha transgenic mice.

Transforming growth factor alpha (TGF-alpha) has been shown to induce liver tumors within 1 year in transgenic male mice in which this potent mitogen is overexpressed. To determine more precisely how TGF-alpha participates in multistep tumorigenesis of the liver, genotoxic (diethylnitrosamine or dimethylnitrosamine) and nongenotoxic (phenobarbital) chemical carcinogens were administered independently to TGF-alpha transgenic mice [line MT42 on a Crl:CD-1(ICR)BR background]. TGF-alpha overexpression dramatically accelerated carcinogen-induced hepatocarcinogenesis in MT42 males but not females. Interestingly, all three chemical agents were found to enhance strongly both hepatic tumor formation and progression in TGF-alpha transgenic male mice. In this study 100%, 90%, and 78% of transgenic males exposed to diethylnitrosamine, dimethylnitrosamine or phenobarbital, respectively, developed tumors between 24 and 32 weeks of age. Moreover, approximately 70% of tumor-bearing transgenic mice from each treatment group had hepatocellular carcinomas; no malignant lesions were found in any carcinogen-treated or untreated nontransgenic mice or in untreated MT42 mice at this age. These results demonstrate that chemical agents as diverse as nitrosamines and phenobarbital act as cocarcinogens with TGF-alpha in the livers of these transgenic mice, indicating that TGF-alpha possesses the unique ability to complement both initiation and promotion in hepatocarcinogenesis. Furthermore, because carcinogen-induced malignant conversion was restricted to transgenic mice, constitutive TGF-alpha overexpression may promote liver tumor progression as well.

Animals↗
PubMed1993

Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis.

Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c-myc complementary DNA and mouse metallothionein 1 promoter-human transforming growth factor alpha complementary DNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing the interaction of nuclear oncogenes and growth factors in tumorigenesis. Coexpression of c-myc and transforming growth factor alpha as transgenes in the mouse liver resulted in a tremendous acceleration of neoplastic development in this organ as compared to expression of either of these transgenes alone. The two distinct cellular reactions that occurred in the liver of the double transgenic mice prior to the appearance of liver tumors were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations. These observations suggest that the interaction of c-myc and transforming growth factor alpha, and possibly other combinations of nuclear oncogenes and growth factors, during development of hepatic neoplasia contributes to the selection and expansion of the preneoplastic cell populations which consequently increases the probability of malignant conversion.

Animals↗
PubMed1993

Targeting expression of a transforming growth factor beta 1 transgene to the pregnant mammary gland inhibits alveolar development and lactation.

Transforming growth factor-beta 1 (TGF-beta 1) possesses highly potent, diverse and often opposing cell-specific activities, and has been implicated in the regulation of a variety of physiologic and developmental processes. To determine the effects of in vivo overexpression of TGF-beta 1 on mammary gland function, transgenic mice were generated harboring a fusion gene consisting of the porcine TGF-beta 1 cDNA placed under the control of regulatory elements of the pregnancy-responsive mouse whey-acidic protein (WAP) gene. Females from two of four transgenic lines were unable to lactate due to inhibition of the formation of lobuloalveolar structures and suppression of production of endogenous milk protein. In contrast, ductal development of the mammary glands was not overtly impaired. There was a complete concordance in transgenic mice between manifestation of the lactation-deficient phenotype and expression of RNA from the WAP/TGF-beta 1 transgene, which was present at low levels in the virgin gland, but was greatly induced at mid-pregnancy. TGF-beta 1 was localized to numerous alveoli and to the periductal extracellular matrix in the mammary gland of transgenic females late in pregnancy by immunohistochemical analysis. Glands reconstituted from cultured transgenic mammary epithelial cells duplicated the inhibition of lobuloalveolar development observed in situ in the mammary glands of pregnant transgenic mice. Results from this transgenic model strongly support the hypothesis that TGF-beta 1 plays an important in vivo role in regulating the development and function of the mammary gland.

Animals↗