Gene and protein expression of glucose transporter 1 and glucose transporter 3 in human laryngeal cancer—the relationship with regulatory hypoxia-inducible factor-1α expression, tumor invasiveness, and patient prognosis

Increased glucose uptake mediated by glucose transporters and reliance on glycolysis are common features of malignant cells. Hypoxia-inducible factor-1α supports the adaptation of hypoxic cells by inducing genes related to glucose metabolism. The contribution of glucose transporter (GLUT) and hypoxia-inducible factor-1α (HIF-1α) activity to tumor behavior and their prognostic value in head and neck cancers remains unclear. The aim of this study was to examine the predictive value of GLUT1, GLUT3, and HIF-1α messenger RNA (mRNA)/protein expression as markers of tumor aggressiveness and prognosis in laryngeal cancer. The level of hypoxia/metabolic marker genes was determined in 106 squamous cell laryngeal cancer (SCC) and 73 noncancerous matched mucosa (NCM) controls using quantitative realtime PCR. The related protein levels were analyzed by Western blot. Positive expression of SLC2A1, SLC2A3, and HIF-1α genes was noted in 83.9, 82.1, and 71.7 % of SCC specimens and in 34.4, 59.4, and 62.5 % of laryngeal cancer samples. Higher levels of mRNA/protein for GLUT1 and HIF-1α were noted in SCC compared to NCM (p<0.05). SLC2A1 was found to have a positive relationship with grade, tumor front grading (TFG) score, and depth and mode of invasion (p<0.05). SLC2A3 was related to grade and invasion type (p<0.05). There were also relationships of HIF-1α with pTNM, TFG scale, invasion depth and mode, tumor recurrences, and overall survival (p<0.05). In addition, more advanced tumors were found to be more likely to demonstrate positive expression of these proteins. In conclusion, the hypoxia/metabolic markers studied could be used as molecular markers of tumor invasiveness in laryngeal cancer.This work was supported, in part, by the statutory fund of the Department of Cytobiochemistry, University of Łódź, Poland (506/811), and by grant fromtheNational Science Council, Poland (N403 043 32/2326)

Expression of hypoxia-associated proteins in sporadic medullary thyroid cancer is associated with desmoplastic stroma reaction and lymph node metastasis and may indicate somatic mutations in the VHL gene.

Medullary thyroid carcinomas (MTCs) are mostly aggressive but slowly growing malignant tumours that metastasize early to loco-regional lymph nodes. Desmoplastic stroma reaction is a strong risk factor associated with lymph node metastases. We evaluated immunohistochemically the expression of two hypoxia-associated proteins, carbonic anhydrase IX (CAIX) and hypoxia-induced factor 1α (HIF1α), and ki-67, intercellular matrix adhesion molecule E-cadherin and the stroma remodelling marker tenascin C in a series of 100 sporadic MTCs and corresponding lymph node metastases, if present. Moderate to strong expression of CAIX was seen in 53 cases, and of HIF1α in 51 cases, showing a strong correlation (p &lt; 0.001; Spearman's coefficient of correlation, 0.59). Expression correlated with the degree of desmoplasia (pCAIX = 0.001 and pHIF1α = 0.001), with tenascin C expression (pCAIX = 0.001,pHIF1α = 0.038), with the ki-67 proliferation index (pCAIX = 0.001, pHIF1α = 0.001) and with the presence of lymph node metastases (pCAIX &lt; 0.001 and pHIF1α = 0.007). The absence of membranous E-cadherin staining was significantly associated with the grade of desmoplasia, tenascin expression and lymph node metastases(p ≤ 0.05) but not with ki67 proliferation index or expression of hypoxia-associated factors. Expression of hypoxia-associated proteins was in most cases identical between primary tumours and lymph node metastases.Two cases showed strong uniform expression of CAIX and HIF1α in the primary tumour as well as in the lymph node metastases, and sequencing revealed mutations in the coding regions of the Von-Hippel–Lindau gene (VHL ).Our findings suggest that despite of the fact that MTCs have only slowly growth, tumour hypoxia plays an important role in the development of loco-regional metastases. Since traditional cytotoxic chemotherapy has only little effect on MTCs, targeting hypoxia-associated and -regulated proteins might be of benefit for patients

Expression of hypoxia-associated proteins in sporadic medullary thyroid cancer is associated with desmoplastic stroma reaction and lymph node metastasis and may indicate somatic mutations in the VHL gene

Medullary thyroid carcinomas (MTCs) are mostly aggressive but slowly growing malignant tumours that metastasize early to loco-regional lymph nodes. Desmoplastic stroma reaction is a strong risk factor associated with lymph node metastases. We evaluated immunohistochemically the expression of two hypoxia-associated proteins, carbonic anhydrase IX (CAIX) and hypoxia-induced factor 1α (HIF1α), and ki-67, intercellular matrix adhesion molecule E-cadherin and the stroma remodelling marker tenascin C in a series of 100 sporadic MTCs and corresponding lymph node metastases, if present. Moderate to strong expression of CAIX was seen in 53 cases, and of HIF1α in 51 cases, showing a strong correlation (p &lt; 0.001; Spearman's coefficient of correlation, 0.59). Expression correlated with the degree of desmoplasia (p CAIX = 0.001 and pHIF1α = 0.001), with tenascin C expression (pCAIX = 0.001, pHIF1α = 0.038), with the ki-67 proliferation index (pCAIX = 0.001, pHIF1α = 0.001) and with the presence of lymph node metastases (pCAIX &lt; 0.001 and pHIF1α = 0.007). The absence of membranous E-cadherin staining was significantly associated with the grade of desmoplasia, tenascin expression and lymph node metastases (p≤0.05) but not with ki67 proliferation index or expression of hypoxia-associated factors. Expression of hypoxia-associated proteins was in most cases identical between primary tumours and lymph node metastases. Two cases showed strong uniform expression of CAIX and HIF1α in the primary tumour as well as in the lymph node metastases, and sequencing revealed mutations in the coding regions of the Von-Hippel-Lindau gene (VHL). Our findings suggest that despite of the fact that MTCs have only slowly growth, tumour hypoxia plays an important role in the development of loco-regional metastases. Since traditional cytotoxic chemotherapy has only little effect on MTCs, targeting hypoxia-associated and -regulated proteins might be of benefit for patients. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley and Sons, Ltd

Neuroendocrine tumors and fibrosis: An unsolved mystery?

Neuroendocrine tumors are a heterogeneous group of slow-growing neoplasms arising mainly from the enterochromaffin cells of thedigestive and respiratory tract. Although they are relatively rare, their incidence is rising. It has long been observed that they oftenare associated with the development of fibrosis, both local and distant. Fibrotic complications, such as carcinoid heart disease andmesenteric desmoplasia, may lead to considerable morbidity or even affect prognosis. The elucidation of the pathophysiology offibrosis would be of critical importance for the development of targeted therapeutic strategies. In this article, the authors review theavailable evidence regarding the biological basis of fibrosis in neuroendocrine tumors. They explore the role of the tumor microenvi-ronment and the interplay between tumor cells and fibroblasts as a key factor in fibrogenesis and tumor development/progression.They also review the role of serotonin, growth factors, and other peptides in the development of carcinoid-related fibrotic reactions