Biomedical subjects

K C Flanders

Publications and source records attributed to K C Flanders.

At least 37 records · Page 2Linked to original sources

PubMed1996

Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease.

In Alzheimer's disease (AD), affected neurons accumulate beta amyloid protein, components of which can induce mouse microglia to express the high-output isoform of nitric oxide synthase (NOS2) in vitro. Products of NOS2 can be neurotoxic. In mice, NOS2 is normally suppressed by transforming growth factor beta 1 (TGF-beta 1). Expression of TGF-beta 1 is decreased in brains from AD patients, a situation that might be permissive for accumulation of NOS2. Accordingly, we investigated the expression of NOS2 in patients with AD, using three monospecific antibodies: a previously described polyclonal and two new monoclonal antibodies. Neurofibrillary tangle-bearing neurons and neuropil threads contained NOS2 in brains from each of 11 AD patients ranging in age from 47 to 81 years. NOS2 was undetectable in brains from 6 control subjects aged 23-72 years, but was expressed in small amounts in 3 control subjects aged 77-87 years. Thus, human neurons can express NOS2 in vivo. The high-output pathway of NO production may contribute to pathogenesis in AD.

Adult↗

PubMed1996

Transforming growth factors-beta protect primary rat hippocampal neuronal cultures from degeneration induced by beta-amyloid peptide.

Treatment of primary rat embryo hippocampal neuronal cultures with 10(-5) M beta-amyloid peptide fragment 25-35 (A beta P) for 24 h resulted in a 60% decrease in cell viability as determined by MTT incorporation. When these cells were treated with 0.1-10 ng/ml of either transforming growth factor-beta (TGF-beta) 1, 2 or 3 for 24 h before exposure to A beta P, there was a 2.9-, 1.9-, and 3.2-fold increase in cell survival, respectively, compared to cells treated with A beta P alone. The viability of cells treated with A beta P and 0.1-10 ng/ml TGF-beta was comparable to that of cells not treated with A beta P. The protective effects were less pronounced at lower TGF-beta concentrations. The protective effects of pretreatment with TGF-beta were less striking in mouse CCL-N-2a and human SK-N-SH neuroblastoma cell lines. When all cells were treated with TGF-beta for 24 h following a 24 h exposure to A beta P, there was a trend toward increased cell viability which was less significant than pretreatment with TGFs-beta. An isoform-specific TGF-beta SELISA showed that primary hippocampal neuronal cultures and the neuroblastoma cell lines secrete all 3 TGF-beta isoforms. Based on our results, we propose that the increased expression of TGF-beta observed in brains of patients with Alzheimer's disease may offer some degree of neuroprotection.

Amyloid beta-Peptides↗

PubMed1996

Altered expression of transforming growth factor-beta 1 in cervical neoplasia as an early biomarker in carcinogenesis of the uterine cervix.

BACKGROUND: Transforming growth factor-beta 1 (TGF-beta 1) is a potent growth inhibitor of epithelial cell growth, but can also stimulate stromal cell growth. Loss of responsiveness to TGF-beta 1 or loss of TGF-beta 1 itself may be important in the progression of cervical intraepithelial neoplasia (CIN) to invasive cervical carcinoma. METHODS. To examine the expression of TGF-beta in early stages of malignant transformation of the uterine cervix, paraffin embedded tissue samples from 11 patients with normal cervical epithelium, 15 with CIN I-III, 12 with microinvasive, and 18 with invasive squamous cell carcinoma were examined using an immunohistochemical technique. Tissues were immunostained with polyclonal antibodies that react with intracellular and extracellular forms of TGF-beta 1. RESULTS: Percent positive staining for the intracellular form of TGF-beta 1 was 100% for normal epithelium, 73.3% for CIN, and 44.1% for invasive carcinomas, (P = 0.002). Percent positive staining for the extracellular form of TGF-beta 1 was 63.6% for stroma underlying normal epithelium, 60% for stroma associated with CIN, and 94.1% for stroma surrounding invasive cancer (P = 0.007). CONCLUSIONS: Decreased expression of intracellular TGF-beta 1 in neoplastic epithelium and increased expression of extracellular TGF-beta 1 in stroma associated with invasive cervical carcinoma suggest that an early event in the neoplastic transformation of cervical epithelia] cells may involve the loss of TGF-beta 1. Tumor progression may be indirectly promoted by TGF-beta 1 secreted into or produced by supporting stromal elements.

Biomarkers, Tumor↗

PubMed1996

Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis.

TGF-beta 1 has been implicated in the pathogenesis of liver disease. The high frequency of detection of the hepatitis B virus X (HBx) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that expression of HBx and TGF-beta 1 may be associated. To test this possibility, we examined the expression of TGF-beta 1 in the liver of transgenic mice expressing the HBx gene. We show that the patterns of expression of TGF-beta 1 and Hbx protein are similar in these mice and that HBx activates transcription of the TGF-beta 1 gene in transfected hepatoma cells. The cis-acting element within the TGF-beta 1 gene that is responsive to regulation by Hbx is the binding site for the Egr family of transcription factors. We further show that the Egr-1 protein associates with the HBx protein, allowing HBx to participate in the transcriptional regulation of immediate-early genes. Our results suggest that expression of Hbx might induce expression of TGF-beta 1 in the early stages of infection and raise the possibility that TGF-beta 1 may play a role in hepatitis B virus pathogenesis.

Amino Acid Sequence↗

PubMed1996

Expression, localization, and function of transforming growth factor-beta s in embryonic chick spinal cord, hindbrain, and dorsal root ganglia.

We have studied the localizations of transforming growth factor-beta (TGF-beta) 2 and 3 immunohistochemically using isoform-specific antibodies and TGF-beta 3 mRNA by in situ hybridization in the nervous system of the 3- to 15-day-old chick embryo with special reference to spinal cord, hindbrain, and dorsal root ganglia (DRG). At embryonic day (E) 3, TGF-beta 3 mRNA as well as TGF-beta 2 and 3 immunoreactivities (IRs) were most prominent in the notochord, wall of the aorta, and dermomyotome. At E5 and E7, strong TGF-beta 2 and 3 IR were seen in or on radial glia of spinal cord and hindbrain. Radial glia in the floor plate region and ventral commissure gave the most intense signal. In the DRG, fiber strands of intense IRs representing extracellular matrix or satellite cells were seen. Neuronal perikarya did not become IR for TGF-beta 2 and 3 until E11, but even then the moderate signals for TGF-beta 3 mRNA could not be specifically localized to the neuronal cell bodies. In E11 and older embryos, spinal cord glial or glial progenitor cells, but not neuronal cell bodies were labeled for TGF-beta 3 mRNA. Immunocytochemistry and western blot analysis indicated that E8 DRG neurons have the TGF-beta receptor type II, and treatment of these cells with NGF induces expression of TGF-beta 3 mRNA. The TGF-beta isoforms 1, 2, and 3 did not promote survival of E8 DRG neurons in dissociated cell cultures. All three TGF-beta isoforms, however, promoted neurite growth from E8 DRG explants, but were less potent than nerve growth factor. Our data suggest identical localizations of TGF-beta 2 and -beta 3 IR in the developing chick and mammalian nervous systems, underscoring the general importance of TGF-beta s in fundamental events of neural development.

Animals↗

PubMed1996

Differential neuronal and astrocytic expression of transforming growth factor beta isoforms in rat hippocampus following transient forebrain ischemia.

Although transforming growth factor-beta (TGF-beta) is known to be multifunctional in many physiological systems, its role in the brain is undergoing elucidation. The situation is made more complex by the presence of multiple isoforms, which may be differentially regulated and have various activities in each particular cell type. Because neurons are dependent on neurotrophic factors for survival, we utilized a rat model of transient forebrain ischemia (TFI) to test the hypothesis that TGF-beta isoforms are important in the hippocampal response to injury. Northern blot analysis demonstrated a differential and temporal alteration in TGF-beta isoform expression following TFI. In-situ hybridization experiments revealed that at day 1 following TFI, there was a strong neuronal increase in the TGF beta-1 transcript but a reciprocal decrease in TGF-beta 2 and -beta 3 transcript levels. Immunohistochemical analysis of all three TGF-beta s demonstrated at day 1 following TFI a loss of the immunoreactive proteins in the vulnerable CA-1 hippocampal neurons, but protein preservation in the CA-2-4 neurons which are more resistant to the ischemic insult. At 3-5 days following TFI, significant extraneuronal changes in TGF-beta isoform expression were also detected. Double-staining experiments with antibody to glial fibrillary acidic protein (GFAP) as a marker for astrocytes, and lectin isolectin B4 Griffonia simplicifolia for microglia, demonstrated increased expression of all TGF-beta isoforms in astrocytes but not microglia. Taken together, these results suggest that the TGF-beta peptides in neurons and astrocytes are important endogenous mediators in the CNS response to ischemic injury.

Animals↗

PubMed1996

Localization of seminal plasma transforming growth factor-beta1 on human spermatozoa: an immunocytochemical study.

OBJECTIVE: To localize immunocytochemically transforming growth factor beta1 (TGF-beta1) in human spermatozoa. DESIGN: Incubation of spermatozoa with anti-TGF-beta1 antiserum at various pH. SETTING: Human volunteers in an academic research institute. PATIENTS: Young healthy fertile men. INTERVENTIONS: Semen specimens were collected. RESULTS: At neutral pH and at physiological pH of seminal plasma, TGF-beta1 immunostaining was detected predominantly at the postacrosomal region of the head, at the neck, and at the middle piece of the tail. Transforming growth factor-beta1 also was found occasionally at the axial filament complex of the connecting piece and the ring. The acrosomal cap section of the head, the principal piece, or the end piece of the tail were immunocytochemically negative for TGF-beta1. The TGF-beta1 immunostaining pattern at acidic pH was similar to that at neutral pH and at physiological pH of seminal plasma, but a greater intensity of immunostaining was found at acidic pH than that at neutral pH. CONCLUSION: These results suggest that an in vivo activation of seminal plasma latent TGF-beta1 may take place in the acidic environment of vagina, which results in a greater amount of activated TGF-beta1 and, in turn, with an enhanced "coating" of TGF-beta1 to spermatozoa.

Humans↗

PubMed1996

TGF-beta rescues target-deprived preganglionic sympathetic neurons in the spinal cord.

Transforming growth factors beta (TGF-beta), a family of pleiotropic cytokines, are widely distributed in the developing and adult nervous system. In order to further determine the neural functions of TGF-beta, we have localized the TGF-beta isoforms 1, 2 and 3 in the adult rat adrenal medulla and studied the neuroprotective capacity of one representative family member, TGF-beta 2, for those spinal cord neurons which innervate adrenal chromaffin cells and which die after destruction of the adrenal medulla. Unilateral electrothermal destruction of the adrenal medulla led to the disappearance of 25% of sympathetic preganglionic neurons, which are located in the intermediolateral (IML) column of thoracic spinal cord segments 7-10 and can be selectively marked by NADPH-diaphorase. The neurons which disappeared following adrenomedullectomy constitute the full set of neurons that innervate the adrenal medulla. Implantation of gelfoam soaked with 0.5 micrograms TGF-beta 2 into the adrenal wound cavity rescued all spinal cord neurons in the IML ipsilaterally to the lesioned side. Cytochrome c was not effective. Injections of [125I]TGF-beta 2 into the adrenal medulla did not result in retrograde transport and subsequent labelling of spinal cord neurons, suggesting that TGF-beta may exert its neuroprotective actions by indirect mechanisms. TGF-beta applied to cultured adrenocortical cells did not overtly increase the amount of mRNA for fibroblast growth factor-2, an established trophic molecule for sympathetic preganglionic spinal cord neurons. The mechanisms by which TGF-beta exerts its neurotrophic effect are therefore unclear. Even so, our data provide the first evidence that TGF-beta may play an important role in vivo in the control of maintenance of a population of spinal cord neurons.

Adrenal Cortex↗

PubMed1996

TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study.

Although it is recognized that three isoforms of transforming growth factor-beta (TGF-beta) exist in mammals, their expression, distribution, and function in injury and repair are not well characterized. Using immunohistochemistry and antibodies to synthetic peptides of TGF-beta 1, TGF-beta 2, and TGF-beta 3, we determined the distribution of TGF-beta isoforms in lung sections with acute and chronic lesions of idiopathic pulmonary fibrosis (IPF), chronic asbestosis and hypersensitivity pneumonitis, as well as non-specific pneumonitis. In lung sections with advanced pulmonary fibrosis and honeycombing, irrespective of the diagnosis, TGF-beta 1 was prominently expressed in epithelial cells and macrophages and was found to be associated with the extracellular matrix. In lungs with early lesions of IPF and only inflammatory changes, TGF-beta 1 was present in alveolar macrophages but TGF-beta 1 was not present in epithelial cells. Small amounts of matrix-associated TGF-beta 1 were present subepithelially in areas of lung sections from patients with IPF with minimal inflammation and no fibrosis. In normal lungs with no evidence of inflammation or fibrosis TGF-beta 1 was not seen in alveolar macrophages, epithelial cells, or extracellularly. TGF-beta 2 and TGF-beta 3 were expressed in alveolar macrophages, epithelial cells, and smooth muscle cells of vessels and bronchi of normal lungs and lungs with both inflammatory and fibrotic changes. Our findings suggest that while TGF-beta 2 and TGF-beta 3 are ubiquitously expressed in the lung, TGF-beta 1 is expressed in epithelial cells of fibrotic lungs where the presence of TGF-beta 1 is not disease-specific but an indication of the chronicity of the injury.

Adult↗

PubMed1995

Distribution of transforming growth factor-beta isoforms in the mammalian retina.

The distribution of transforming growth factor-beta (TGF-beta) was examined in the posterior segment of the monkey, human, and feline eye using antisera to TGF-beta 1, TGF-beta 2, or TGF-beta 3. A number of different antibodies, tissue processing methods, immunolocalization techniques, and microscopic imaging systems were used in an attempt to gain a more comprehensive picture of TGF-beta isoform distribution in the retina and retinal pigmented epithelium (RPE). The results are generally consistent in identifying one or more of the three TGF-beta isoforms in the cytoplasm of a small, overlapping subset of cells. RPE cells, photoreceptors, Mueller cells, ganglion cells, hyalocytes, and cells associated with choroidal and retinal vessels are all represented in this immunoreactive population. No evidence of extracellular labeling was noted. The intracellular distribution of the three isoforms is distinctly different in photoreceptors. Anti-TGF-beta 1 precursor and anti-TGF-beta 2 immunoreactivity is confined primarily to rod outer segments, whereas anti-TGF-beta 3 immunoreactivities are restricted to mitochondria within inner segments. In the RPE, clusters of anti-TGF-beta 2 positive cytoplasmic granules are located near the cells' lateral borders, whereas anti-TGF-beta 3 labeling is concentrated apically. These results provide baseline information from which new hypotheses regarding the function(s) of TGF-beta isoforms in the retina can be formulated.

Animals↗

PubMed1995

Transforming growth factor-beta: neuronal and glial expression in CNS degenerative diseases.

We have previously shown that the brains of patients with Alzheimer's disease (AD) express transforming growth factor (TGF)-beta 2 in neurofibrillary tangle (NFT)-bearing neurons and reactive astrocytes. The present study was undertaken to determine whether other neurodegenerative diseases were also associated with an alteration of the TGF-beta's. The immunohistochemical expression of TGF-beta 1, -2 and -3 was assessed in the brains of patients with progressive supranuclear palsy (n = 2), amyotrophic lateral sclerosis (n = 3), Lewy body disease (n = 5), Parkinson's disease (n = 1), Shy-Drager syndrome (n = 1), Pick's disease (n = 3), lobar atrophy (n = 1), and corticobasal degeneration (n = 2). Our results were compared to norms for controls (n = 8). We found expression of TGF-beta 2 in both NFT bearing neurons and tangle-bearing glial cells in progressive supranuclear palsy and in neurons with age-related NFT formation. Widespread staining of reactive astrocytes for TGF-beta 2 was observed in all degenerative diseases. TGF-beta 1 and -3 staining was not selectively altered in these diseases. We conclude that induction of TGF-beta 2 may be an intrinsic part of the processes that underlie NFT formation and reactive gliosis in a variety of neurodegenerative diseases.

Adult↗

PubMed1995

The effects of retinoid status on TGF beta expression during mouse embryogenesis.

In a previous study we investigated the effects of RA excess on TGF beta protein localization in early postimplantation stages of mouse development. Here we extend this investigation by comparing the effects of retinoid deficiency with those of excess, and by comparing the effects of altered retinoid status on TGF beta protein and RNA transcript distribution. In vitamin A-deficient embryos, TGF beta 1 RNA and protein distribution were both unaltered compared with controls; conversely, TGF beta 2 protein levels were reduced while RNA levels remained normal. In RA-treated embryos, the previous study showed that intracellular TGF beta 1 levels were decreased, while those of extracellular TFG beta 1 were initially decreased but subsequently increased; here we found that TGF beta 1 RNA transcript levels were reduced following exposure to RA excess. TGF beta 2 showed a clear disparity between the effects of RA excess on protein and RNA transcript levels: RNA transcript distribution was unchanged or showed a slight increase in RA-treated embryos, whereas the previous results showed greatly reduced protein levels. The new results provide further evidence for interaction between retinoids and TGF beta s during mouse development, and indicate that retinoids are capable of differentially regulating TGF beta isoforms through mechanisms involving different stages in the process of TGF beta synthesis and secretion. The long-term nature of the effects of transient exposure to RA excess suggests that the mechanisms of RA-TGF beta interaction may be indirect.

Animals↗

PubMed1995

Autoinduction of mRNA and protein expression for transforming growth factor-beta S in cultured cardiac cells.

Although transforming growth factor-beta s (TGF-beta s) are expressed widely in both adult and embryonic rat heart, both mRNA and protein expression increase following ischemic injury. Furthermore, exogenous administration of TGF-beta decreases cardiac damage following ischemia-reperfusion in rats. We have found that treatment of primary cultures of neonatal rat cardiomyocytes or cardiac fibroblasts with TGF-beta 1, 2, or 3 results in increased expression of TGF-beta 1, 2, and 3 mRNA. TGF-beta 2 was generally the least effective isoform in inducing TGF-beta expression. In cardiac fibroblasts mRNA expression of all TGF-beta s increased 2-3-fold following 1 h of treatment and decreased to control levels by 8 h which was accompanied by a 2.5- and 2.3-fold increase in TGF-beta 1 and 2 protein secretion, respectively. By 48 h of treatment mRNA levels for TGF-beta s 2 and 3 were less than 10% of control levels. In cardiomyocytes two-five-fold increases in mRNA levels were observed following 1-24 h of TGF-beta 1 treatment, but TGF-beta 1 and 3 mRNA levels returned to control values by 48 h while TGF-beta 2 mRNA expression remained elevated. TGF-beta 1 and 2 protein secreted by the cardiac myocytes was increased 2.9- and 1.7-fold, respectively. Autoinduction of TGF-beta s may play a beneficial role in cardiac wound healing by sustaining transient increases in TGF-beta levels from either endogenous synthesis or exogenous application.

Animals↗

PubMed1995

Immunohistochemical localization of transforming growth factor-beta 1 in Kaposi's sarcoma.

Immunohistochemical localization of transforming growth factor beta 1 (TGF-beta 1) was studied in Kaposi's sarcoma (KS) tissues obtained from autopsy and biopsy materials of patients with and without acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV) infection. There was no difference in the localization and distribution of TGF-beta 1 in KS tissues regardless of the HIV-1 status of the patients. Rabbit polyclonal antibodies to synthetic peptides, corresponding to the first 30 amino acids of mature TGF-beta 1, anti-LC(1-30), and anti-CC(1-30), were used for localization of intracellular and extracellular TGF-beta 1. An antibody to a peptide corresponding to amino acids 266 to 278 of the TGF-beta 1 precursor sequence anti-Pre(266 to 278) was used to detect the TGF-beta 1 precursor and the latency-associated peptide. Intracellular mature TGF-beta 1 was demonstrated in mononuclear cells, presumably macrophages, within KS tumors but not in spindle-shaped KS cells. Extracellular mature TGF-beta 1 was localized in the basement membranes of blood vessels and fibrous capsules of KS tumors. Intracellular reactivity to anti-Pre was localized in vascular smooth muscle cells and pericytes within the tumor, in variable proportions of spindle-shaped KS cells, and also in macrophage-like cells. These cells appear to be the production sites of TGF-beta 1, which may exert paracrine as well as autocrine proliferative effects.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Characterization of murine pregnancy decidua transforming growth factor beta. I. Transforming growth factor beta 2-like molecules of unusual molecular size released in bioactive form.

A novel type of bioactive transforming growth factor beta 2 (TGF beta 2)-related immunosuppressive activity, lower in molecular mass (20-23 kDa) than a conventional TGF beta 2 standard (25 kDa), has been shown to be released by non-T non-B suppressor cells of murine decidua into fetal bovine serum (FBS)-containing tissue culture medium during a 48-h incubation at 37 degrees C. Substitution of a serum-free medium has allowed direct PAGE-Western blotting and the demonstration in supernatant (prior to incubation at 37 degrees C) of a TGF beta 2-immunoreactive doublet at a higher molecular mass (26 and 27 kDa) than the standard but with apparent immunosuppressive activity. When decidua were incubated in serum-free medium at 37 degrees C, immunosuppressive activity in the supernatant increased to peak at 18 h in association with the appearance of the previously described lower molecular mass species of molecule. The doublet did not appear to be the result of glycosylation of a conventional 25-kDa TGF beta 2 and could be converted into the lower molecular mass form by incubation for 18 h at 37 degrees C, with pH 4.5 but not with pH 7.5 buffer; this incubation in the absence of decidual cells was not accompanied by increased immunosuppressive activity. This transformation could be blocked by a brief heating of the supernatant to 80 degrees C for 10 min to destroy enzymes present in supernatant prior to mixing with the acidic buffer, but biologic activity neutralizable by anti-TGF beta 2 was retained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

A subset of patients with recurrent spontaneous abortion is deficient in transforming growth factor beta-2-producing "suppressor cells" in uterine tissue near the placental attachment site.

PROBLEM: To determine if patients with unexplained recurrent miscarriage have a deficiency of decidual immunosuppressor cells that produce transforming growth factor beta type 2, as has been found in mice with abortion due to rejection and/or trophoblast failure. METHODS: Decidual biopsy specimens were taken as near to the placental attachment site as possible under ultrasound guidance from first trimester legal termination (control) patients with recurrent miscarriage and non-viable pregnancy, and from patients with sporadic missed abortion. The tissue was tested for TGF beta-2+ suppressor cells by in situ hybridization, immunohistochemistry, and analysis of supernatants. RESULTS: TGF beta-2-related suppressor molecules similar but not identical to those identified in pregnant mice were released by decidual lymphoid cells. Fifty percent of 14 recurrent miscarriage patients showed a lack of suppressor cells and 59% were subnormal in comparison to 20 controls and 5 sporadic miscarriage patients, where 80-85% of the patients had detectable suppressor cells. CONCLUSIONS: Suppressor cell deficiency is compatible with a role for rejection and/or trophoblast failure in some patients with recurrent miscarriage. Presence of suppressor cells in most patients with missed abortion (4/5) is compatible with an alternative cause of fetal death, similar to findings reported in genetic fetal death mice.

Abortion, Habitual↗

PubMed1995

Altered expression of transforming growth factor-beta in Alzheimer's disease.

We compared immunohistochemical expression of the transforming growth factor-betas (TGF-beta 1, TGF-beta 2, and TGF-beta 3) using brain tissue from patients with nondominantly inherited Alzheimer's disease (NDAD) (n = 9), autosomal dominantly inherited Alzheimer's disease with linkage to 14q24.3 (FAD-14) (n = 4), and cognitively normal controls (n = 10) to determine whether their pathologic changes are associated with an altered distribution of the TGF-betas. We found increased expression of TGF-beta 2 in large, tangle-bearing neurons with widespread staining of glia in NDAD and FAD-14 patients compared with control cases. This result was confirmed with sandwich ELISA assays of brain tissue, which showed TGF-beta 2 levels in AD and NDAD to average 3.2 times the average level of control cases. Despite proximity of TGF-beta 1 and TGF-beta 3 to the sites of susceptibility loci on chromosomes 19 and 14, we did not find that TGF-beta 1 and TGF-beta 3 were selectively altered in any AD subtypes. However, selective induction of TGF-beta 2 may occur in NDAD and FAD-14.

Aged↗

PubMed1995

Transforming growth factor-beta 1: comparative immunohistochemical localization in human primary and metastatic prostate cancer.

BACKGROUND: We have shown previously that primary prostate cancer demonstrates significant extracellular accumulation of transforming growth factor-beta 1 (TGF-beta 1). To further investigate the potential role of TGF-beta 1 in prostate cancer progression, we evaluated an expanded series of primary prostatic carcinomas and associated lymph node metastases. EXPERIMENTAL DESIGN: Prostate tissue samples from 37 patients were examined. Three were organ donors, all less than 30 years of age, whose prostates were included as normal controls. Eighteen had undergone radical prostatectomy and pelvic lymph node dissection. Eleven were without evidence of metastasis, whereas seven were found to have prostate cancer within at least one of their pelvic lymph nodes. Sixteen had undergone transurethral resection of the prostate for benign disease, yet all had prostate cancer within the resected specimen (15 were stage T1b; 1 was stage T1a). Twelve of the patients with stage T1b disease underwent pelvic lymph node dissection and implantation of radioactive gold seeds. All 12 had prostate cancer in at least one lymph node. All specimens were examined for the level of expression and localization of TGF-beta 1 by immunohistochemistry using Ab that distinguish intracellular from extracellular TGF-beta 1. RESULTS: Normal prostate tissue and benign prostatic hyperplasia demonstrated negative or weak intracellular and extracellular staining for TGF-beta 1. By comparison, 29 of 34 primary prostate cancers showed extensive extracellular TGF-beta 1 staining with pronounced intracellular accumulation within epithelial cells in 13 of 34 patients. There was no difference in the staining pattern for extracellular TGF-beta 1 between primary cancers with and without pelvic lymph node metastases. However, in primary cancers without pelvic lymph node metastases, only 1 of 15 patients showed strong intracellular staining for TGF-beta 1 compared with 12 of 19 primary tumors with metastatic disease. In addition, only 2 of 19 lymph node metastases demonstrated weak extracellular TGF-beta 1 staining, but all 19 contained intracellular TGF-beta 1. CONCLUSIONS: These findings confirm our previous observation that prostate cancer exhibits enhanced intracellular and extracellular accumulation of TGF-beta 1 relative to normal prostate tissue and benign prostatic hyperplasia. In addition, our study documented a significantly more pronounced accumulation of intracellular TGF-beta 1 in primary prostate cancer with metastasis than in primary tumors without metastasis. Moreover, although the pattern of intracellular TGF-beta 1 staining observed in the primary tumor is maintained in the metastasis, a lack of extracellular accumulation of TGF-beta 1 in the metastatic site was noted. This differential pattern may be biologically important and could conceivably reflect a role for TGF-beta 1 in disease progression.

Adenocarcinoma↗