Reduced expression of hyaluronan is a strong indicator of poor survival in oral squamous cell carcinoma
Introduction
Oral cancer is the sixth most common cancer worldwide. The most common type of oral cancer is squamous cell carcinoma (SCC) accounting almost nine out of 10 oral malignancies.1 The prognostic evaluation and the decisions on treatment strategy are mainly based on the TNM-classification.2 The survival depends on several factors: the stage of the disease (size of the primary lesion, local extension, lymph node involvement, distant metastasis), the site of the primary tumour, the adequacy of the initial treatment, the Karnofsky performance status, and the histological differentiation of the malignancy.1 Despite advanced treatment strategies the survival of oral cancer patients has not changed over the last decades. In search for accurate tools by which the prognosis of an individual oral SCC could be predicted tumour suppressor genes,3, 4, 5 cell proliferation,6 angiogenesis7 and cell adhesion molecules8, 9 have been studied in oral carcinoma.
Hyaluronan (HA) is an unbranched polysaccharide consisting of repeating disaccharide units of N-acetyl-glucosamine and glucuronic acid.10 It is almost ubiquitously distributed in various human tissues. The highest concentration of HA is found within soft connective tissues, predominantly in the skin.11 HA is synthesised at the cell surface by the membrane-bound enzyme hyaluronan synthase.12 Many functions have been attributed to HA including cell migration, proliferation and differentiation during embryonic development, wound healing and inflammation.10 Notably, HA fragments are angiogenic, stimulating tumour neovascularisation and aiding in tumour metastasis.13 Studies from several epithelial neoplasms show that HA has a significant role in tumour progression and metastasis.14, 15, 16, 17, 18, 19 It has turned out that the majority of squamous cell carcinomas are characterised by a high percentage of HA-positive cancer cells20, 21 in contrast to adenocarcinomas, which seem to display a low percentage of HA-positive cancer cells. Because of the intriguing association of SCC and HA and the need to better predict the behaviour of an individual tumour, we evaluated the expression of HA and its prognostic value in a series of 151 oral SCCs with complete follow-up data.
Section snippets
Patients
A total of 151 oral SCC patients with adequate archival tumour material were studied. These patients were selected from a consecutive series of 239 patients diagnosed and treated for oral SCC at Kuopio University Hospital and Jyväskylä Central Hospital, Finland between 1979 and 1998, excluding cases with insufficient tumour material or follow-up data.
The clinical data from each case were reviewed by two clinicians: one oncologist and one otolaryngologist. The tumour staging was carried out
HA staining in normal epithelium and dysplasias
Normal epithelium showed a strong staining for HA. A homogeneous staining pattern was present in all layers of the epithelium except the most superficial layers which were negative (Fig. 1a). In dysplastic epithelium (n=27) a distinct difference from the normal staining pattern was evident. The strong HA positivity extended up to the most superficial layer (Fig. 1b). Localised areas with reduced, intracellular and irregular signal for HA were observed in moderate (n=11) and high grade
Discussion
Several studies have shown the importance of HA in the progression of various human cancers.16, 17, 18, 19, 20, 21 Although many tumours are enriched with HA, they show considerable differences in HA expression depending on the cellular origin, as well as on the histological type.24 HA expression is generally high in normal squamous cells and most carcinomas of squamous cell origin as shown also in the present study. This is in contrast to non-stratified epithelia, which show no or only slight
Acknowledgements
The study has been supported by Kuopio and Tampere University Hospital EVO funding and the Northern Savo Cancer Fund. The authors thank Mrs. A. Parkkinen for the skilful immunohistochemical assistance and Mrs. P. Halonen for assistance with statistical analysis.
References (30)
- et al.
Prevalence of p53, bcl-2, and Ki-67 immunoreactivity and of apoptosis in normal oral epithelium and in premalignant and malignant lesions of the oral cavity
J Oral Maxillofac Surg
(2002) - et al.
Proliferative activity and loss of function of tumour suppressor genes as 'biomarkers' in diagnosis and prognosis of benign and preneoplastic oral lesions and oral squamous cell carcinoma
Br. J. Oral Maxillofac. Surg.
(1998) - et al.
Hyaluronan and homeostasis: a balancing act
J. Biol. Chem.
(2002) - et al.
Hyaluronan synthases
J. Biol. Chem.
(1997) - et al.
High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer
Eur J Cancer
(2001) - et al.
Hyaluronan in peritumoural stroma and malignant cells associates with breast cancer spreading and predicts survival
Am J Pathol.
(2000) - et al.
Histochemical localisation of hyaluronate in human oral epithelium using a specific hyaluronate-binding probe
Arch Oral Biol.
(1990) - et al.
Localisation of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe
J. Invest. Dermatol.
(1988) - et al.
Degradation of newly synthesized high molecular mass hyaluronan in the epidermal and dermal compartments of human skin in organ culture
J. Invest. Dermatol.
(1991) - et al.
CD44-mediated uptake and degradation of hyaluronan
Matrix Biol.
(2002)
TNM Classification of Malignant Tumours
Overexpression of p53 is an early event in the tumourigenesis of oral squamous cell carcinomas
Anticancer Res.
Predicting tumour metastasis in patients with oral cancer by means of the proliferation marker Ki67
J Oral Sci.
Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma
J Clin Oncol
Cited by (59)
Histopathological Factors in Oral Squamous Cell Carcinoma—Should a Clinician Look Beyond Clinical Staging?
2021, Journal of Oral and Maxillofacial SurgeryPattern of tumor invasion, stromal inflammation, angiogenesis and vascular invasion in oral squamous cell carcinoma – A prognostic study
2021, Current Problems in CancerCitation Excerpt :With reference to the prognosis of the patients no statistical significance was observed between the histopathological groups. Most authors have established significant correlations between lower histologic differentiation and poorer prognosis.49-53 but others did not find such association.54-56 There was a statistically significant difference observed between the prognosis of cases and various scores of pattern of tumor invasion (P= 0.043).
Staging and grading of oral squamous cell carcinoma: An update
2020, Oral OncologyCellular hyaluronan is associated with a poor prognosis in renal cell carcinoma
2020, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Hyaluronan content varies in solid tumors. Studies have shown that cellular hyaluronan contents were lower in squamous cell carcinoma of the mouth, skin, and larynx and in cutaneous melanomas, compared to their benign counterparts [12–15]. In addition, hyaluronan accumulations were observed in the peritumoural stroma in pancreatic, breast, gastric, ovarian, and prostate adenocarcinomas [16–20].
Revisiting the hallmarks of cancer: The role of hyaluronan
2020, Seminars in Cancer Biology
- 1
Present Address: Department of Pathology, Tampere University Hospital and Tampere University, PO Box 2000, FIN-33521, Tampere, Finland.