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Bone morphogenetic protein 6 expression in oral cavity squamous cell cancer is associated with bone invasion.

ABSTRACT: To evaluate bone invasion, survival, and expression of bone morphogenetic protein-6 (BMP-6) in oral cavity cancer in the context of known biomarkers indicative of poor prognosis.Molecular expression study combined with retrospective chart review of corresponding patients at a tertiary care center.Between 2000 and 2009, a total of 197 patients underwent resection for oral cavity squamous cell carcinoma. Of these, 30 pathologic specimens were chosen for further molecular analysis. These 30 patients were separated into three groups (10 per group) based on American Joint Committee on Cancer (AJCC) staging and staging based on size alone (TAJCC /SIZE ). The first group consisted of tumors staged as T2 /2 based on size less than 4 cm and that had no evidence of bone invasion. The T2 /4 group consisted of tumors that were upstaged from T2 based on bone invasion. The T4 /4 group consisted of tumors that were large with and without bone invasion. The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), BMP-6, and epidermal growth factor receptor (EGFR) was examined using immunohistochemistry techniques. Patient demographics, tumor characteristics, survival, and recurrence were compared.Average follow-up was 21 months. Expression of BMP-6 was significantly higher in the T2 /4 cohort (tumor less than 4 cm with bony invasion) than the larger tumors without bone invasion (T4 /4 cohort, P = .05). In addition, increased BMP-6 expression correlated with aggressive behavior in the smaller tumors. Furthermore, increased EGFR expression positively correlated with increased levels of BMP-6.Increased expression of BMP-6 in oral cavity cancer may affect bone invasion.

SUBMITTER: Kejner AE

PROVIDER: S-EPMC3805669 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Bone morphogenetic protein 6 expression in oral cavity squamous cell cancer is associated with bone invasion.

Kejner Alexandra E AE Burch M Benjamin MB Sweeny Larissa L Rosenthal Eben L EL

The Laryngoscope 20130701 12

<h4>Objectives/hypothesis</h4>To evaluate bone invasion, survival, and expression of bone morphogenetic protein-6 (BMP-6) in oral cavity cancer in the context of known biomarkers indicative of poor prognosis.<h4>Study design</h4>Molecular expression study combined with retrospective chart review of corresponding patients at a tertiary care center.<h4>Methods</h4>Between 2000 and 2009, a total of 197 patients underwent resection for oral cavity squamous cell carcinoma. Of these, 30 pathologic spe ...[more]

PMID: 23775772

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Project description:BackgroundThe molecular mechanisms involved in the invasion of bone by oral squamous cell carcinomas (OSCC) are poorly understood, and little is known about the role of cancer-associated fibroblasts (CAF), the presence of which confers a poor prognosis.MethodsClinicopathological data from 277 OSCC cases involving bone resections were reviewed, and 32 cases thoroughly analysed histologically. Immunohistochemistry was used to examine αSMA, RANKL and OPG. Western blotting and qPCR were used to assess myofibroblast (CAF-like) differentiation, RANKL and OPG expression in vitro, and RANKL secretion was analysed by ELISA. Osteoclastogenesis was examined using TRAP staining, multinucleation and pit forming assays.ResultsFibrous stroma intervened between tumour and bone in the majority of cases, with no direct contact between cancer cells and bone. RANKL and OPG, two proteins key to regulating bone resorption, were expressed in tumour cells as well as fibrous stroma adjacent to bone and αSMA-positive myofibroblastic CAF were consistently seen infiltrating into bone ahead of tumour cells. Human primary osteoblasts cultured with conditioned media from human OSCC-derived cells and human primary CAF showed a significant increase in RANKL and a decline in OPG mRNA expression. RANKL secretion was significantly increased in primary oral fibroblasts induced to differentiate into a CAF-like phenotype by transforming growth factor-β1 (TGF-β1) treatment and in primary CAF. Indirect co-culture of murine macrophages with conditioned media from CAF (experimentally derived and isolated from OSCCs) resulted in a marked increase in osteoclastogenesis (in excess of that provoked by cancer cells) determined by tartrate-resistant acid phosphatase activity, multinucleation and resorption pit formation.ConclusionsThis study is the first to describe a functional role for CAFs in bone invasion and turnover, identifying a novel potential therapeutic target and diagnostic indicator in this difficult to treat bone invasive malignancy.

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Bone morphogenetic protein 6 expression in oral cavity squamous cell cancer is associated with bone invasion.

Publications

Bone morphogenetic protein 6 expression in oral cavity squamous cell cancer is associated with bone invasion.

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