Decreased expression of transforming growth factor beta receptors on head and neck squamous cell carcinoma tumor cells

doi:10.1016/S0002-9610(96)00305-4

The American Journal of Surgery

Volume 172, Issue 6, December 1996, Pages 641-645

https://doi.org/10.1016/S0002-9610(96)00305-4 Get rights and content

Background

Transforming growth factor beta (TGF-β) has antiproliferative effects on normal and neoplastic cells that express specific TGF-β receptors. We hypothesize that diminished expression of TGF-β and/or its receptors may contribute to the uncontrolled proliferation of head and neck squamous cell carcinoma (HNSCCA) cancer cells.

Methods

Using immunohistochemical techniques, we characterized the expression of TGF-β isoforms and TGF-β receptors, TGF-β(RI) and TGF-β(RII), in HNSCCA. Tumor production of TGF-β was evaluated in culture supernatants from a cytokine-stimulated HNSCCA tumor line (HTB-43).

Results

All control specimens displayed strong cell-associated staining of TGF-β as well as both receptors. Forty-seven of 47 cancer specimens exhibited positive staining for TGF-β in the tumor matrix. Forty of the 47 cancer specimens demonstrated no expression of TGF-β(RI), and 43 of the 47 expressed no TGF-β(RII). Only interleukin 1 alpha (IL-1α) and IL-1β induced significant TGF-β expression from the HTB-43 cells.

Conclusions

Decreased expression of TGF-β receptors may play a significant role in the pathogenesis of HNSCCA by allowing uncontrolled cell proliferation.

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Oral squamous cell carcinoma and many squamous cell carcinomas of the head and neck (SCCHN) occur as a consequence of multiple molecular events induced by the effects of carcinogens from habits such as tobacco consumption and influenced by environmental factors—viruses in some instances—against a background of heritable susceptibility. Consequent genetic damage affects many chromosomes and genes, and it is the accumulation of these genetic changes that leads to such cell dysregulation that growth becomes autonomous and invasive mechanisms develop, leading to carcinoma in some instances. In these cases, enhanced function of oncogenes, impaired function of tumor suppressor genes (TSG) or their products, or increased telomerase activity is involved. Overexpression of oncogenes, especially those on chromosomes 11 and 17, has been implicated in the carcinogenesis of SCCHN. TSGs, particularly 3p, where the TSGs are involved, are as yet unidentified. 9p21, where p16 is the main target TSG, and 17p13, where p53 is the major target TSG, have been incriminated.
Expression of TGF-β type II receptors in the olfactory epithelium and their regulation in TGF-α transgenic mice
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Citation Excerpt :
For example, low concentrations of BMP4 promote neurogenesis by supporting survival of NCAM+ ORNs [50] and several BMPs, including BMP4 at high concentrations, inhibit neurogenesis by decreasing progenitor cell proliferation [51]. Loss of TGF-βRII expression is associated with the dysregulation of proliferation exhibited by several types of epithelial cancers, including head and neck squamous cell carcinoma [9]. The level of PGP 9.5 expression appears to be similar in the TGF-α T and NT mice, suggesting that the expression of a neuronal phenotype is unaffected by the downregulated expression of TGF-βRII.
Numerous in vitro studies of neurogenesis of olfactory receptor neurons (ORNs) suggest that transforming growth factor (TGF)-β promotes the maturation/differentiation of olfactory progenitors. We demonstrate that in vivo both mature and immature ORNs, and possibly a basal neuronal progenitor cell, express the TGF-β type II receptor (TGF-βRII), suggesting that these cells are targets for TGF-β signaling. In a previous study of neurogenesis in the OE of TGF-α overexpressing transgenic (T) mice, we observed an apparent reduction in the expression of olfactory marker protein (OMP), a marker of terminal differentiation in ORNs in T mice compared to nontransgenic (NT) littermate controls; this was confirmed by Western blotting and immunohistochemistry. In contrast, there was no apparent difference between T and NT mice in the intensity of immunoreactivity for a neuronal marker, protein gene product 9.5. Because TGF-α overexpression has been reported to affect TGF-β signaling in other epithelia, we compared the expression of the TGF-β type II receptor (TGF-βRII) in T and NT mice. The intensity of TGF-βRII immunoreactivity on ORNs was substantially reduced in T compared to NT mice. Similar reductions in TGF-βRII expression in vomeronasal receptor neurons and in other epithelia in the nasal cavity of T mice were also observed. Taken together, these results indicate that TGF-β signaling regulates terminal differentiation of ORNs in vivo and suggest ways in which interactions between TGF-α and TGF-β signaling pathways may interact in the OE.
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Carcinogenesis is the result of a series of genetic mutations resulting in unregulated growth of a clone of cells and the development of malignant lesion that is largely monoclonal though, with the evolution of further genetic changes, there develops a degree of heterogeneity in the tumour. DNA technology, especially allelic imbalance (loss of heterozygosity) studies have identified chromosomal changes in oral carcinoma and head and neck squamous cell carcinoma (SCCHN), suggestive of the involvement of tumour suppressor genes (TSGs), particularly in chromosomes 3, 9, 11 and 17. The regions most commonly identified have included 3p, especially 3p14.2 (FHIT); 3p24, and 3p21.3, where the TSGs involved are as yet unidentified; 9p21 where p16 (INK4A/MTS-1] is the main target TSG; and 17p13 where p53 is the major target TSG. Over-expression of oncogenes, genes mainly involved in cell signalling, especially those on chromosome 11 (PRAD-1 in particular) and 17 (H-ras) and mutations in DNA repair genes, have also been implicated in the carcinogenesis of SCCHN.
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^***: Accepted for podium presentation at the International Conference on Head and Neck Cancer Toronto, Canada, April 1996.

View full text

Decreased expression of transforming growth factor beta receptors on head and neck squamous cell carcinoma tumor cells***

Background

Methods

Results

Conclusions

Cancer Treatment Reviews

Exp Cell Res

Am J Surg

Progr Growth Factor Res

J Biol Chem

Enhanced Tumor Cell Expression of Tumor Necrosis Factor Receptors in Head and Neck Squamous Cell Carcinoma

Am J Surg

Interleukin-1 Receptor Antagonist in Head and Neck Squamous Cell Carcinoma

Arch Ota HNS

Interleukin 8 expression by head and neck squamous cell carcinoma

Arch Otolaryngol Head Neck Surg

Transforming growth factor TGF-β1 inhibits retinoblastoma gene expression but not pRB phasphorylation in TGF-β1 growth stimulated colon carcinoma cells

Oncogene

Differential sensitivity of human colonic adenoma and carcinoma cells to transforming growth factor (TGF-β): Converstion of an Adenoma Cell line to a Tumorigenic Phenotype is accompanied a reduced response to the inhibitory effects of TGF-β

Oncogene