transforming-growth-factor-alpha and Adenocarcinoma--Clear-Cell

This study aimed to investigate serum levels of epidermal growth factor (EGF), transforming growth factor α (TGF-α), and c-erbB2 in patients with ovarian cancer.. In this retrospective cohort study, the study and control groups were composed of 43 women with a prediagnosis of ovarian cancer and 43 healthy women, respectively. Blood samples from all women were obtained and studied by enzyme-linked immunosorbent assay kits for EGF, TGF-α, and c-erbB2. After surgery of the study group, ovarian cancer was confirmed and compared with control group. Stage, grade, and histological types were defined after histopathologic examination, and subgroups were constructed and compared.. Serum EGF, TGF-α, and c-erbB2 levels were significantly increased in study group compared with those in the control group (P < 0.001). There were no differences in serum levels of EGF, TGF-α, and c-erbB2 among all stages, grades, and histological types of ovarian cancer. If 47.90 pg/mL was selected as the cutoff value, EGF has an 80% sensitivity and a 65% specificity for detecting ovarian cancer. The cutoff value of 41,095.00 pg/mL for TGF-α has a 90% sensitivity and a 72% specificity for detecting ovarian cancer. The c-erbB2 level of 4.63 pg/mL as the cutoff value has an 83% sensitivity and a 76% specificity for predicting ovarian cancer.. Serum levels of EGF, TGF-α, and c-erbB2 may be used for diagnosing ovarian cancer.

Topics: Adenocarcinoma, Clear Cell; Adenocarcinoma, Mucinous; Biomarkers, Tumor; Case-Control Studies; Cystadenocarcinoma, Serous; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Humans; Middle Aged; Neoplasm Grading; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Receptor, ErbB-2; Retrospective Studies; ROC Curve; Transforming Growth Factor alpha

The mechanism that regulates the growth of ovarian clearcell adenocarcinoma (CCA) are not well understood. We investigated the role of several growth factors that bind to membrane tyrosine kinase receptors and added them to the ovarian CCA cell lines KK, RMG-1, and HAC-II to evaluate their effect on growth and cellular invasion. Epidermal growth factor and transforming growth factor-alpha significantly stimulated the growth and invasion of CCA cell lines in vitro. ZD1839, an epidermal growth factor receptor-tyrosine kinase inhibitor, decreased the growth and invasion of CCA cell lines in vitro and in vivo inhibited the growth of xenografts of the CCA cell line RMG-1. Severe combined immunodeficient mice bearing RMG-1 xenografts treated with ZD1839 survived for longer than the untreated control group. From these findings, we conclude that ZD1839 may offer a new and effective treatment for ovarian CCA.

Topics: Adenocarcinoma, Clear Cell; Animals; Antineoplastic Agents; Cell Division; Cytokines; Endothelial Growth Factors; ErbB Receptors; Female; Gefitinib; Growth Substances; Humans; Immunoenzyme Techniques; In Vitro Techniques; Intercellular Signaling Peptides and Proteins; Lymphokines; Mice; Mice, SCID; Ovarian Neoplasms; Phosphorylation; Protein-Tyrosine Kinases; Quinazolines; Transforming Growth Factor alpha; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Mutations of the VHL tumor suppressor gene occur in patients with VHL disease and in the majority of sporadic clear cell renal carcinomas (VHL(-/-) RCC). Loss of VHL protein function is associated with constitutive expression of mRNAs encoding hypoxia-inducible proteins, such as vascular endothelial growth factor. Overproduction of angiogenic factors might explain why VHL(-/-) RCC tumors are so highly vascularized, but whether this overproduction is sufficient for oncogenesis still remains unknown. In this report, we examined the activity of transforming growth factor-alpha (TGF-alpha), another VHL-regulated growth factor. We show that TGF-alpha mRNA and protein are hypoxia-inducible in VHL(-/-) RCC cells expressing reintroduced VHL. In addition to its overexpression by VHL(-/-) RCC cells, TGF-alpha can also act as a specific growth-stimulatory factor for VHL(-/-) RCC cells expressing reintroduced wild-type VHL, as well as primary renal proximal tubule epithelial cells, the likely site of origin of RCC. This role is in contrast to those of other growth factors overexpressed by VHL(-/-) RCC cells, such as vascular endothelial growth factor and TGF-beta1, which do not stimulate RCC cell proliferation. A TGF-alpha-specific antisense oligodeoxynucleotide blocked TGF-alpha production in VHL(-/-) RCC cells, which led to the dependence of those cells on exogenous growth factors to sustain growth in culture. Growth of VHL(-/-) RCC cells was also significantly reduced by a drug that specifically inhibits the epidermal growth factor receptor, the receptor through which TGF-alpha stimulates proliferation. These results suggest that the generation of a TGF-alpha autocrine loop as a consequence of VHL inactivation in renal proximal tubule epithelial cells may provide the uncontrolled growth stimulus necessary for the initiation of tumorigenesis.

Topics: Adenocarcinoma, Clear Cell; Cell Division; Cell Hypoxia; Enzyme Inhibitors; ErbB Receptors; Gene Expression Regulation; Genes, Tumor Suppressor; Growth Substances; Humans; Insulin; Kidney Neoplasms; Ligases; Oligodeoxyribonucleotides, Antisense; Proteins; Quinazolines; Selenium; Transferrin; Transforming Growth Factor alpha; Tumor Cells, Cultured; Tumor Suppressor Proteins; Tyrphostins; Ubiquitin-Protein Ligases; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

The clear cell and the papillary types of human renal cell carcinoma (RCC) are distinct tumour entities with marked differences in their biological properties. Because growth factors are considered to affect profoundly the biological behaviour of malignant tumours, we compared the expression and function of transforming growth factor (TGF)-alpha and fibroblast growth factor (FGF) in both types of RCCs. Both in vivo and in vitro expression of TGF-alpha, epidermal growth factor-receptor (EGF-R), FGF-2 and FGF type 3- and 4-receptors was found in RCCs of both types. However, marked differences between clear cell and papillary RCCs became evident for TGF-alpha secretion, which could be demonstrated in 20 out of 24 (83%) clear cell RCCs but in only two out of four (50%) papillary tumours. Moreover, the mean TGF-alpha secretion rate in clear cell RCCs significantly (P<0. 05) exceeded that of papillary RCCs. Because the expression of growth factor receptors could not prove the corresponding signalling cascades were functional, tumour cell proliferation was tested after exposure to exogenous TGF-alpha or FGF-1. These experiments demonstrated that papillary RCCs did not respond significantly to exogenous TGF-alpha or FGF-1, whereas eight (33%) (TGF-alpha) and 11 (46%) (FGF-1) out of 24 clear cell RCCs responded with significant (P<0.05) growth stimulation. In conclusion, our investigation presents data indicating that TGF-alpha and FGF are functionally involved in the progression of clear cell RCCs, directly stimulating proliferation by autocrine and/or paracrine actions. In contrast, TGF-alpha and FGF did not directly stimulate the proliferation of our papillary RCCs, thereby suggesting functional defects or a blockade in the corresponding signalling cascades. This differential functionality might contribute to the more aggressive behaviour of clear cell RCCs.

Topics: Adenocarcinoma, Clear Cell; Adenocarcinoma, Papillary; Blotting, Northern; Carcinoma, Renal Cell; Fibroblast Growth Factors; Flow Cytometry; Humans; Immunohistochemistry; Kidney Neoplasms; Receptors, Fibroblast Growth Factor; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor alpha; Tumor Cells, Cultured