transforming-growth-factor-beta and Carcinoma--Neuroendocrine

Neuroendocrine neoplasms (NENs) are a heterogeneous family of malignancies whose proliferation is partially dependent on growth factors secreted by the microenvironment and the tumor itself. Growth factors which were demonstrated to be important in experimental models of NENs include EGF (epidermal growth factor), TGF (transforming growth factor) α, TGFβ and CTGF (connective tissue growth factor). EGF and TGFα bind to the EGF receptor to stimulate an intact RAS/RAF/MAPK pathway, leading to the transcription of genes associated with cell proliferation, invasion and metastasis. Theoretically, TGFα stimulation can be inhibited at several points of the MAPK pathway, but success is limited to NEN models and is not evident in the clinical setting. TGFβ1 stimulates TGFβ receptors (TGFβRI and TGFβRII) resulting in inhibition of neuroendocrine cell growth through SMAD-mediated activation of the growth inhibitor P21(WAF1/CIP1). Although some NENs are inhibited by TGFβ1, paradoxical growth is seen in experimental models of gastric and small intestinal (SI) NENs. Therapeutic targeting of TGFβ1 in NENs is therefore complicated by uncertainty of the effect of TGFβ1 secretion on the direction of proliferative regulation. CTGF expression is associated with more malignant clinical phenotypes in a variety of cancers, including NENs. CTGF promotes growth in gastric and SI-NEN models, and is implicated as a mediator of local and distant fibrosis caused by NENs of enterochromaffin cell origin. CTGF inhibitors are available, but their anti-proliferative effect has not been tested in NENs. In summary, growth factors are essential for NEN proliferation, and although interventions targeting these proteins are effective in experimental models, only limited clinical efficacy has been identified.

Topics: Animals; Carcinoma, Neuroendocrine; Connective Tissue Growth Factor; ErbB Receptors; Humans; Signal Transduction; Transforming Growth Factor alpha; Transforming Growth Factor beta

The bone morphogenetic proteins (BMP) are phytogenetically conserved proteins, which are essential for embryonic development. Bone morphogenetic protein-2 (BMP-2) was recently shown to be expressed in a small sample of lung carcinomas. Studies have suggested that BMP-2 may enhance tumor growth. The present study examined which BMP family members are expressed in non-small cell lung carcinomas (NSCLC). Furthermore, the frequency of BMP-2 overexpression and the types of lung carcinomas expressing BMP-2 were determined.. Tissue samples were obtained from the operating room and frozen in liquid nitrogen. Samples included metastatic NSCLC, benign lung tumors, adenocarcinoma, squamous cell carcinoma, bronchioloalveolar, and neuroendocrine carcinomas. Paired normal lung tissues served as the controls. The BMP-2, BMP-4, BMP-6, BMP-7, and growth differentiation factor 5 (GDF-5) expressions were examined by Western blot analysis.. The BMP-4, BMP-6, BMP-7, and GDF-5 were infrequently expressed in NSCLC. The BMP-2 was expressed in 41 of 42 NSCLC with minimal expression in normal lung tissue; BMP-2 was expressed 17 fold higher than that of normal lung tissue. The BMP-2 was over-expressed in all subtypes of NSCLC, including neuroendocrine carcinomas. The BMP-2 expression was similar between squamous cell carcinomas and adenocarcinomas; however, bronchioloalveolar carcinomas tended to have a lower level of expression. The BMP-2 was not significantly expressed in benign lung tumors.. Bone morphogenetic protein-2 is the predominant family member expressed in NSCLC. The BMP-2 is overexpressed in the majority of human lung carcinomas independent of cell type.

Topics: Adenocarcinoma; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein 6; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Growth Differentiation Factor 5; Humans; Lung Neoplasms; Transforming Growth Factor beta

Topics: Animals; Carcinoma, Neuroendocrine; DNA-Binding Proteins; Gastrointestinal Neoplasms; Humans; Neoplasm Proteins; Pancreatic Neoplasms; Proto-Oncogene Proteins; Rats; Receptors, Transforming Growth Factor beta; Smad Proteins; Trans-Activators; Transforming Growth Factor beta

Human colorectal neuroendocrine cell carcinoma (NEC) is a rare disease with a poor prognosis. The biological behavior of NEC remains poorly understood.. We established two new NEC cell lines from a patient with rectal neuroendocrine carcinoma, NECS-P and NECS-L from the primary tumor and a liver metastasis, respectively. We investigated the biological differences between the two cell lines to study the mechanisms involved in liver metastasis.. There was no difference between NECS-P and NECS-L in the morphological, ultrastructural and immunohistochemical studies. After addition of TGF-beta(1), the doubling times of NECS-P were increased in a dose-dependent manner relative to untreated cells, whereas TGF-beta(1) had no effect on NECS-L. The attachment and chemotactic response of the two cell lines were not enhanced by TGF-beta(1). The invasive capacity and the production of matrix metalloproteinase-2 (MMP-2) were significantly increased only in NECS-L following the addition of TGF-beta(1). When anti-MMP-2 antibody was added to the medium with TGF-beta(1), NECS-L invasion was inhibited.. It is considered that these differences are important to understand the mechanisms of liver metastasis of NEC.

Topics: Carcinoma, Neuroendocrine; Cell Division; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Rectal Neoplasms; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured