Genome wide profiling in oral squamous cell carcinoma identifies a four genetic marker signature of prognostic significance

Vincent‐Chong, Vui King; Salahshourifar, Iman; Woo, Kar Mun; Anwar, Arif; Razali, Rozaimi Mohamad; Gudimella, Ranganath; Rahman, Zainal Ariff Abdul; Ismail, Siti Mazlipah; Kallarakkal, Thomas George; Ramanathan, Anand; Mustafa, Wan Mahadzir Wan; Abraham, Mannil Thomas; Tay, Keng Kiong; Zain, Rosnah Binti

doi:10.1371/journal.pone.0174865

Cited by 30 publications

(18 citation statements)

References 40 publications

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“…Recently, LTBP3 has been identified as one of a number of genes with copy number alterations in patients with oral squamous cell carcinomas. 52 The data from our orthotopic murine model for head and neck cancer employing HEp-3 epidermoid carcinoma cells ( Figure 6 ) indicated that expression of LTBP-3 is important for the levels of spontaneous metastasis of cancer cells from primary buccal tumors to lungs, but not for late stages of metastatic colonization associated with vascular arrest, survival, extravasation and lung colonization, all of which follow the intravasation step.…”

Section: Resultsmentioning

confidence: 91%

LTBP3 promotes early metastatic events during cancer cell dissemination

et al. 2018

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Latent Transforming Growth Factor β (TGFβ) Binding Proteins (LTBPs) are important for the secretion, activation and function of mature TGFβ, especially so in cancer cell physiology. However, specific roles of the LTBPs remain understudied in the context of the primary tumor microenvironment. Herein, we investigated the role of LTBP-3 in the distinct processes involved in cancer metastasis. By using three human tumor cell lines of different tissue origin (epidermoid HEp-3 and prostate PC-3 carcinomas and HT-1080 fibrosarcoma) and several metastasis models conducted in both mammalian and avian settings, we show that LTBP-3 is involved in the early dissemination of primary cancer cells, namely in the intravasation step of the metastatic cascade. Knockdown of LTBP-3 in all tested cell lines led to significant inhibition of tumor cell intravasation, but did not affect primary tumor growth. LTBP-3 was dispensable in the late steps of carcinoma cell metastasis that follow tumor cell intravasation, including vascular arrest, extravasation and tissue colonization. However, LTBP-3 depletion diminished the angiogenesis-inducing potential of HEp-3 cells in vivo, which was restorable by exogenous delivery of LTBP-3 protein. A similar compensatory approach rescued the dampened intravasation of LTBP-3-deficient HEp-3 cells, suggesting that LTBP-3 regulates the induction of the intravasation-supporting angiogenic vasculature within developing primary tumors. Using our recently developed microtumor model, we confirmed that LTBP-3 loss resulted in the development of intratumoral vessels with an abnormal microarchitecture incompatible with efficient intravasation of HEp-3 carcinoma cells. Collectively, these findings demonstrate that LTBP-3 represents a novel oncotarget that has distinctive functions in the regulation of angiogenesis-dependent tumor cell intravasation, a critical process during early cancer dissemination. Our experimental data are also consistent with the survival prognostic value of LTBP3 expression in early stage head and neck squamous cell carcinomas, further indicating a specific role for LTBP-3 in cancer progression towards metastatic disease.

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Section: Resultsmentioning

confidence: 91%

LTBP3 promotes early metastatic events during cancer cell dissemination

et al. 2018

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“…Amplification of this region of 11q has been previously reported in HNSCC patients and shown to be correlated with worse outcomes. 8,9 Furthermore, alterations of CCND1 and/or cyclin-dependent kinase inhibitor 2A (CDKN2A) (both leading to deregulation of the G1/S cell cycle checkpoint pathway), were strongly associated with rapid engraftment.…”

mentioning

confidence: 99%

Patient-derived xenografts: a promising resource for preclinical cancer research

Karamboulas

Ailles

2019

Molecular & Cellular Oncology

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Patient-derived xenograft tumors retain molecular and histopathological features of the originating tumor and are useful preclinical tools for drug discovery and assessment. We recently reported that ‘rapid’ engraftment of head and neck squamous cell carcinoma samples is highly prognostic and correlates with deregulation of the G1/S checkpoint. Tumors with genetic alterations in cyclinD1 (CCND1) and/or cyclin-dependent kinase inhibitor 2A (CDKN2A) are more likely to respond to abemaciclib.

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“…Loss in FHIT and RB1 were the only well described HNSCC associated mutations (25) detected in TADE and which were absent from both the tumor and NE, suggesting this TADE is an independent clone and not related to the tumor. Interestingly, the size of a loss on 3p26.3 in NE that increased in this TADE would be important to investigate further for possible role in early genetic event in the NE, since a loss in this region has been suggested to be an independent prognostic factor in OSCC patients (26,27).…”

Section: Genetic Alterations Reveal Both Intratumoral Clonal Heterogementioning

confidence: 99%

“…Surprisingly, one of the genetic events-loss and/or LOH of 3p21.3-was common in all the five NE. Inactivating mutations in this region have been a consistent finding in cancers, especially HNSCC, and have been associated with early development of dysplastic lesions in HNSCC (13,27,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). The clinical significance of this genetic event in NE is unknown and warrants further investigation.…”

Section: Normal Epithelium (Ne)mentioning

confidence: 99%