Prognostic implications of mandibular invasion in oral cancer

Ash, Cecil S.; Nason, Richard W.; Abdoh, Ahmed A.; Cohen, Mark A.

doi:10.1002/1097-0347(200012)22:8<794::aid-hed8>3.0.co;2-w

Cited by 66 publications

(56 citation statements)

References 22 publications

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“…at ASPET Journals on May 12, 2018 molpharm.aspetjournals.org Downloaded from are known for their ability to promote osteolysis (Ash et al, 2000). As expected, RANKL increased cell migration across the membrane by 100% (Fig.…”

Section: Hts System For Agents Regulating Gene Expression 923supporting

confidence: 62%

“…As mentioned above, MMP-9 also contributes to bone resorption with some osteolytic malignancies including breast, multiple myeloma, and oral cancers (Ash et al, 2000;Van Valckenborgh et al, 2004;Guise et al, 2005). For cancers metastatic to the bone, osteoclasts and their precursors (macrophage lineage) rather than cancer cells express MMP-9 in response to cytokines, including receptor activator of nuclear factor-B ligand (RANKL), resulting in bone lysis, cancer cell colonization/growth, and further recruitment of preosteoclasts to the remodeling bone (Guise et al, 2005).…”

Section: Integration Of An Mmp-9 Promoter Into An Openmentioning

confidence: 93%

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A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

Nair

Ávila

et al. 2007

Mol Pharmacol

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Aberrant gene expression is one of the driving forces for cancer progression and is considered an ideal target for chemical intervention. Although emerging bioluminescence reporter systems allow high-throughput searches for small molecules regulatory for gene expression, frequent silencing of reporter genes by epigenetic mechanisms hinders wide application of this drug discovery strategy. Here we report a novel system that directs the integration of a promoter-reporter construct to an open chromosomal location by Flp-mediated homologous recombination, thereby overcoming reporter-gene silencing. Using this system, we have screened more than 8000 compounds in the DIVERSet chemical library for repressors of a matrix metalloproteinase-9 (MMP-9) promoter and identified 5-methyl-2-(4-methylphenyl)-1H-benzimidazole (MPBD) inhibitory for MMP-9 gene expression. Consistent with this effect, MPBD inhibits MMP-9-dependent invasion of UMSCC-1 oral cancer cells, preosteoclast migration, and receptor activator of nuclear factor-B ligand-induced osteoclast activity over concentration ranges that repressed MMP-9 expression. Mechanistic studies indicated that MPBD antagonizes AP-1 function by inhibiting its transactivation activity. We conclude that the Flp-mediated homologous recombination system to direct reporter integration into open chromatin regions represents a novel strategy allowing for the development of high-throughput systems screening for lead compounds targeting aberrant gene expression in cancer.

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Section: Hts System For Agents Regulating Gene Expression 923supporting

confidence: 62%

Section: Integration Of An Mmp-9 Promoter Into An Openmentioning

confidence: 93%

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

Nair

Ávila

et al. 2007

Mol Pharmacol

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“…These findings differ from those of previous studies that distinguished between cortical and medullary invasion, but found no prognostic significance on multivariate analyses. 5,10 This may reflect differences in covariate selection and limited statistical power (type II error), as both studies had small sample size in comparison with the current analysis. Interestingly, when bone invasion was classified as simply present or absent, it was not a significant independent predictor of overall (P ¼ .225) or disease-specific survival (P ¼ .221).…”

Section: Discussionmentioning

confidence: 87%

“…Whereas some authors have reported an association with adverse outcomes on univariate analysis, [3][4][5][6][7] other studies did not support this finding. [8][9][10] Furthermore, multivariate analyses taking into account potential confounding factors such as tumor size and involved margins have suggested that bone invasion is not an independent predictor of survival. [4][5][6] Unfortunately, the majority of the studies to date were limited by small sample sizes and failed to distinguish between cortical and medullary bone invasion, making reliable conclusions difficult.…”

mentioning

confidence: 99%

The prognostic and staging implications of bone invasion in oral squamous cell carcinoma

Ebrahimi

Murali

Gao

et al. 2011

Cancer

102

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BACKGROUND: A study was undertaken to determine whether bone invasion is an independent prognostic factor in oral squamous cell carcinoma (SCC) after taking into account the extent of bone invasion. METHODS: The study was a retrospective review of 498 patients with oral SCC undergoing surgery with curative intent, 102 of whom had pathologically proven bone invasion. Bone invasion was categorized as absent, cortical, or medullary and tested for association with disease control and survival. RESULTS: After adjusting for potential confounding factors in multivariate analysis, there was no association between cortical invasion and overall (P ¼ .48) or disease-specific survival (P ¼ .63). In contrast, medullary invasion was an independent predictor of reduced overall (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1; P ¼ .006) and disease-specific survival (HR, 2.1; 95% CI, 1.2-3.6; P ¼ .01), and this appeared to result from an increased risk of distant metastatic failure (P ¼ .037) rather than local (P ¼ .51) or regional recurrence (P ¼ .14). Within the subset of patients with medullary invasion, survival differed significantly according to tumor size (P ¼ .029). CONCLUSIONS: Patients with oral SCC and bone invasion have widely variable outcomes depending on the depth of bone invasion and tumor size. The results suggest that the current American Joint Committee on Cancer staging system, which classifies all tumors invading through cortical bone as T4, has limited prognostic utility. The authors recommend a revision of the T staging system such that tumors are classified as T1 to T3 based on size and then upstaged by 1 T stage in the presence of medullary bone invasion. Cancer 2011;117:4460-7.

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“…1A and B) (4)(5)(6). Gingival SCC may eventually directly invade the mandible, a feature associated with a worse prognosis.…”

Section: Introductionmentioning

confidence: 99%

The RANKL/RANK system as a therapeutic target for bone invasion by oral squamous cell carcinoma

Jimi

Shin

Furuta

et al. 2013

International Journal of Oncology

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Abstract. Squamous cell carcinomas (SCCs) of the gingiva frequently invade the mandible or maxilla; this invasion is associated with a worse prognosis. The bone destruction associated with carcinomal invasion is mediated by osteoclasts rather than directly by the carcinoma. Therefore, if the cellular and molecular mechanisms by which oral SCC regulates bone invasion were known, it could inform the development of new therapeutic targets. Recently, dysregulation of the functional equilibrium in the receptor activator of NF-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) triad has been shown to be responsible for osteolysis associated with the development of malignant tumors in bone sites. Furthermore, the administration of OPG or soluble RANK prevents bone metastasis by cancer cells. In this review, we discuss recent findings indicating that bone invasion by oral SCC is mediated via RANKL/RANK and may be successfully prevented by RANKL inhibition.

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Prognostic implications of mandibular invasion in oral cancer

Cited by 66 publications

References 22 publications

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

The prognostic and staging implications of bone invasion in oral squamous cell carcinoma

The RANKL/RANK system as a therapeutic target for bone invasion by oral squamous cell carcinoma

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