Molecular events in relapsed oral squamous cell carcinoma: Recurrence vs secondary primary tumor

Gleber‐Netto, Frederico O.; Braakhuis, Boudewijn J.M.; Triantafyllou, Asterios; Takes, Robert P.; Kelner, Natalie; Rodrigo, Juan P.; Strojan, Primož; Poorten, Vincent Vander; Rapidis, Alexander D.; Rinaldo, Alessandra; Brakenhoff, Ruud H.; Ferlito, Alfio; Kowalski, Luiz Paulo

doi:10.1016/j.oraloncology.2015.04.016

Cited by 33 publications

(27 citation statements)

References 54 publications

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“…Our rationale for selection of this in vivo model is as follows. As the OIN to OSCC transition can be extremely brief at former resection sites, formation of microtumor foci is a realistic clinical concern [2, 3]. Provided this scenario, secondary chemopreventives would be required to inhibit OSCC tumor development, albeit on a smaller scale than currently tested.…”

Section: Discussionmentioning

confidence: 99%

“…Following management of the primary OSCC tumor (surgical resection often accompanied by radiation and/or chemotherapy) patients are managed by close clinical follow up supplemented with CT, PET, or MRI imaging. Despite vigilant monitoring and well-recognized risk factors for recurrence (close margins, immunosuppression, high histologic grade, deep tumor extension) over one third of patients develop life-threatening and often untreatable recurrent OSCCs [2, 3]. Replacement of this “watchful waiting” strategy with a well-tolerated and effective strategy to prevent OSCC recurrence (secondary chemoprevention) could benefit patients.…”

Section: Introductionmentioning

confidence: 99%

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Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype

Mallery

Wang

Santiago

et al. 2017

Cancer Prevention Research

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Over 1/3 of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells’ reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives i.e. the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic) and the humanized monoclonal antibody to the IL-6R receptor tocilizumab (TOC, reduces IL-6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL-6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally-delivered TOC, TOC+4-HPR and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents employ diverse mechanisms to disrupt tumorigenesis at multiple venues i.e. intracellular, tumor cell-ECM and tumor microenvironment; beneficial qualities for secondary chemopreventives.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype

Mallery

Wang

Santiago

et al. 2017

Cancer Prevention Research

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“…However, early detection of recurrent disease is challenging due to lymph nodal micrometastases and radiation or surgery induced fibrosis and inflammation, obscuring residual or recurrent tumor tissue [1–3]. Accurate and timely detection of locoregional metastases and recurrent disease is pivotal as survival rates rapidly decline with late detection and delayed salvage surgery [4, 5]. With recent developments in molecular diagnostics, the use of (blood-based) genetic biomarkers is growing in a wide variety of cancer types [6].…”

Section: Introductionmentioning

confidence: 99%

Droplet digital PCR for detection and quantification of circulating tumor DNA in plasma of head and neck cancer patients

Ginkel

Huibers

et al. 2017

BMC Cancer

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BackgroundDuring posttreatment surveillance of head and neck cancer patients, imaging is insufficiently accurate for the early detection of relapsing disease. Free circulating tumor DNA (ctDNA) may serve as a novel biomarker for monitoring tumor burden during posttreatment surveillance of these patients. In this exploratory study, we investigated whether low level ctDNA in plasma of head and neck cancer patients can be detected using Droplet Digital PCR (ddPCR).Methods TP53 mutations were determined in surgically resected primary tumor samples from six patients with high stage (II-IV), moderate to poorly differentiated head and neck squamous cell carcinoma (HNSCC). Subsequently, mutation specific ddPCR assays were designed. Pretreatment plasma samples from these patients were examined on the presence of ctDNA by ddPCR using the mutation-specific assays. The ddPCR results were evaluated alongside clinicopathological data.ResultsIn all cases, plasma samples were found positive for targeted TP53 mutations in varying degrees (absolute quantification of 2.2–422 mutational copies/ml plasma). Mutations were detected in wild-type TP53 background templates of 7667–156,667 copies/ml plasma, yielding fractional abundances of down to 0.01%.ConclusionsOur results show that detection of tumor specific TP53 mutations in low level ctDNA from HNSCC patients using ddPCR is technically feasible and provide ground for future research on ctDNA quantification for the use of diagnostic biomarkers in the posttreatment surveillance of HNSCC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3424-0) contains supplementary material, which is available to authorized users.

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“…The exposure to chemical, physical or biological agents with mutagenic and carcinogenic properties leads mutated keratinocytes to proliferate and invade the connective tissue. OSCCs responsiveness to chemotherapy is low likely due to the heterogeneity of tumor cell population; the high local recurrence rate of this disease results in a 5 year survival rate of only 40–50% [2, 3]. …”

Section: Introductionmentioning

confidence: 99%

Inhibition of αvβ3 integrin induces loss of cell directionality of oral squamous carcinoma cells (OSCC)

et al. 2017

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The connective tissue formed by extracellular matrix (ECM) rich in fibronectin and collagen consists a barrier that cancer cells have to overpass to reach blood vessels and then a metastatic site. Cell adhesion to fibronectin is mediated by αvβ3 and α5β1 integrins through an RGD motif present in this ECM protein, thus making these receptors key targets for cell migration studies. Here we investigated the effect of an RGD disintegrin, DisBa-01, on the migration of human fibroblasts (BJ) and oral squamous cancer cells (OSCC, SCC25) on a fibronectin-rich environment. Time-lapse images were acquired on fibronectin-coated glass-bottomed dishes. Migration speed and directionality analysis indicated that OSCC cells, but not fibroblasts, showed significant decrease in both parameters in the presence of DisBa-01 (1μM and 2μM). Integrin expression levels of the α5, αv and β3 subunits were similar in both cell lines, while β1 subunit is present in lower levels on the cancer cells. Next, we examined whether the effects of DisBa-01 were related to changes in adhesion properties by using paxillin immunostaining and total internal reflection fluorescence TIRF microscopy. OSCCs in the presence of DisBa-01 showed increased adhesion sizes and number of maturing adhesion. The same parameters were analyzed usingβ3-GFP overexpressing cells and showed that β3 overexpression restored cell migration velocity and the number of maturing adhesion that were altered by DisBa-01. Surface plasmon resonance analysis showed that DisBa-01 has 100x higher affinity for αvβ3 integrin than forα5β1 integrin. In conclusion, our results suggest that the αvβ3 integrin is the main receptor involved in cell directionality and its blockage may be an interesting alternative against metastasis.

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Molecular events in relapsed oral squamous cell carcinoma: Recurrence vs secondary primary tumor

Cited by 33 publications

References 54 publications

Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype

Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype

Droplet digital PCR for detection and quantification of circulating tumor DNA in plasma of head and neck cancer patients

Inhibition of αvβ3 integrin induces loss of cell directionality of oral squamous carcinoma cells (OSCC)

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