Negative/Low Expression of the Met/Hepatocyte Growth Factor Receptor Identifies Papillary Thyroid Carcinomas with High Risk of Distant Metastases¹

Abstract

To investigate the clinical impact of Met/hepatocyte growth factor receptor (HGF-R) expression in thyroid cancer we studied 163 thyroid carcinomas (129 papillary, 21 follicular, and 13 anaplastic) from patients followed-up for 25-147 months postthyroidectomy. Forty-nine thyroid adenomas were also studied. Met/HGF-R expression was evaluated by semiquantitative immunohistochemistry, measuring both the proportion (scale of 0 -5) and the intensity (scale, 0 -5) of stained cells and calculating a total score (scale of 0 -10).Met/HGF-R was absent in the normal thyroid tissue, absent or focally expressed in follicular and anaplastic tumors, and expressed at various levels in most papillary carcinomas, including microcarcinomas. Papillary carcinomas were thus categorized as having negative/low Met/HGF-R (n ϭ 50; total score, Յ5) or high Met/HGF-R expression (n ϭ 70; total score, Ͼ5). High Met/HGF-R was inversely associated with vascular invasion (P ϭ 0.0308), but not with other prognostic factors. Negative/low Met/HGF-R expression was the most effective predictor by multivariate Cox analysis of distant metastases (hazard ratio ϭ 9.71; P ϭ 0.0036), higher than extrathyroid invasion (hazard ratio ϭ 4.25; P ϭ 0.0181), age (Յ45 vs. Ͼ45 yr; hazard ratio ϭ 3.99; P ϭ 0.0099), and vascular invasion (hazard ratio ϭ 3.19; P ϭ 0.0358). These findings suggest a role for Met/HGF-R in papillary thyroid cancer and its clinical use to select patients with a high risk of distant metastases. (J Clin Endocrinol Metab 82: 2322-2328, 1997

Tyrosine kinase inhibitor STI571 enhances thyroid cancer cell motile response to Hepatocyte Growth Factor

“…Remarkably, these STI571-sensitive mechanisms do not appear to be present in normal thyroid cells. This dierent behavior of cancer and normal thyroid cells could not be correlated with levels of Met receptor expression (Bel®ore et al, 1997;Di Renzo et al, 1995). We observed the enhancing eect of STI571 in thyroid cancer cells TPC-1 and WRO, which expressed the Met receptor at a level comparable to that of normal immortalized cells DR-15 (Figure 2 and Table 1).…”

“…Another possibility is that the HGF-independent constitutive activity of Met receptor found in thyroid cancer cells (Costantino et al, manuscript in preparation;Bergstrom et al, 1999, 2000 and Figure 5) may trigger a negative feedback loop to inhibit Met receptor signaling. The existence of these negative pathways may help to explain the apparent paradox in which a better prognosis was associated with a subset of thyroid tumors that overexpress the Met receptor (Bel®ore et al, 1997). The unraveling of the STI571-sensitive pathways on cell motility may be important for the understanding of thyroid tumor progression and the metastatic potential of thyroid cancer cells.…”

The IGF-I/IGF-I Receptor Pathway: Implications in the Pathophysiology of Thyroid Cancer

“…Therefore, TSH suppression with l-thyroxine administration is of limited efficacy in poorly differentiated or undifferentiated thyroid carcinomas. Early studies performed in thyroid cell cultures have shown that the mitogenic effects of TSH are small in the absence of other growth factors, although they are greatly enhanced by the presence of insulin or IGF-I at physiological concentrations [120][121][122][123][124].…”

Activating Transcription Factor-1-mediated Hepatocyte Growth Factor-induced Down-regulation of Thrombospondin-1 Expression Leads to Thyroid Cancer Cell Invasion

“…Because Met is not expressed or only expressed at low level in the normal thyroid, aberrant expression and autocrine or mutational activation of c-Met receptor in papillary cancer suggest a possible role for the HGF-Met axis in tumor development and progression (15)(16)(17).…”