metastat and Thyroid-Neoplasms

Mechanisms of invasion in thyroid cancer remain poorly understood. We hypothesized that signaling via the epidermal growth factor receptor (EGFR) stimulates thyroid cancer cell invasion by altering the expression and cleavage of matrix metalloproteinases (MMPs). Papillary and follicular carcinoma cell lines were treated with EGF, the EGFR tyrosine kinase inhibitor AG1478, and the MMP inhibitors GM-6001 and Col-3. Flow cytometry was used to detect EGFR. In vitro invasion assays, gelatin zymography, and quantitative reverse transcription-PCR were used to assess the changes in invasive behavior and MMP expression and activation. All cell lines were found to overexpress functional EGFR. EGF stimulated invasion by thyroid cancer cells up to sevenfold (P<0.0001), a process that was antagonized completely by AG1478 and Col-3, partially by GM-6001, but not by the serine protease inhibitor aprotinin. EGF upregulated expression of MMP-9 (2.64- to 8.89-fold, P<0.0001) and membrane type-1 MMP (MT1-MMP, 1.97- to 2.67-fold, P<0.0001). This effect was blocked completely by AG1478 and partially by Col-3. The activation of MMP-2 paralleled MT1-MMP expression. We demonstrate that MMPs are critical effectors of invasion in the papillary and follicular thyroid cancer cell lines studied. Invasion is regulated by signaling through EGFR, an effect mediated by augmentation of gelatinase expression and activation. MMP inhibitors and growth factor antagonists may be effective tumoristatic agents for the treatment of aggressive thyroid carcinomas.

Topics: Adenocarcinoma, Follicular; Aprotinin; Blotting, Western; Carcinoma, Papillary; Cell Differentiation; Dipeptides; Enzyme Activation; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; Flow Cytometry; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Neoplasm Invasiveness; Protease Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Quinazolines; Reverse Transcriptase Polymerase Chain Reaction; Serine Proteinase Inhibitors; Tetracyclines; Thyroid Neoplasms; Tumor Cells, Cultured; Tyrphostins

Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic properties, developed anemia while on treatment. All of these patients were enrolled on an approved Phase I clinical trial at the National Cancer Institute. Three of these patients had bone marrow examinations that revealed ringed sideroblasts. This paper describes these cases. Am. J. Hematol. 67:51-53, 2001. Published 2001 Wiley-Liss, Inc.

Topics: Adenocarcinoma, Follicular; Adult; Anemia, Sideroblastic; Antibiotics, Antineoplastic; Antineoplastic Agents; Bone Marrow; Female; Humans; Male; Middle Aged; Tetracycline; Tetracyclines; Thyroid Neoplasms