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Ng Y.-K.,Chinese University of Hong Kong | Wong E.Y.L.,Chinese University of Hong Kong | Lau C.P.Y.,Chinese University of Hong Kong | Chan J.P.L.,Chinese University of Hong Kong | And 9 more authors.
Investigational New Drugs | Year: 2012

Recent studies revealed an unexpected role of the neurotrophin receptor pathway, BDNF/TrkB signaling, in cancer metastasis and anoikis (i.e. detachment-induced cell death). Survival of cancer cells in detached state (known as anoikis-resistance) is known to be pre-requisite for metastasis. Nasopharyngeal carcinoma (NPC), an endemic head and neck cancer in Southeast Asia, is highly invasive, metastatic, and etiologically associated with Epstein-Barr virus (EBV, an oncovirus) infection. Mechanistic studies on the invasive/metastatic nature of NPC can facilitate the development of anti-metastatic therapy in NPC. Thus far, the role of BDNF/TrkB signaling in virus-associated human cancer is unclear. Here, using multiple cell line models of NPC with EBV-association (HONE-1-EBV, HK1-LMP1 and C666-1), we investigated the potential involvement of BDNF/TrkB signaling in cellular migration and anoikis-resistant characteristics of NPC. We found that all three EBV-associated NPC cell lines tested were intrinsically anoikis-resistant (i.e. survived in detached state) and expressed both BDNF and TrkB. BDNF stimulation induced cellular migration, but not proliferation of these cells. Further, we examined if pharmacologic targeting of anoikis-resistance of NPC cells can be achievable by a proof-of-concept Trk inhibitor, K252a, in these EBV-associated NPC models. Our results demonstrated that K252a, was able to attenuate BDNFinduced migration and proliferation of NPC cells. More importantly, we demonstrated for the first time that K252a harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced cell death) against EBVassociated human cancer cells, namely NPC cells. This proofof- concept study demonstrated that K252a, a Trk inhibitor, can potentially be used as an anoikis-sensitizing agent in NPC. © Springer Science+Business Media, LLC 2010.

Loong H.H.,Prince of Wales Hospital | Ma B.B.Y.,Sir Pao Center for Cancer | Ma B.B.Y.,Chinese University of Hong Kong
Hong Kong Journal of Radiology | Year: 2012

Mortality from metastatic colorectal cancer has declined over the past decade, partly due to improvement in survival secondary to incorporation of targeted biologics in the treatment paradigm. We are now witnessing a new wave of new therapeutic options that may further improve survival outcomes for patients with metastatic colorectal cancer. This review will discuss recently matured data on the treatment outcomes of new anti-angiogenic targeted therapies in metastatic colorectal cancer and how they may affect the practice of oncology. © 2012 Hong Kong College of Radiologists.

Wong J.H.T.,Sir Pao Center for Cancer | Lui V.W.Y.,Sir Pao Center for Cancer | Umezawa K.,Keio University | Ho Y.,Sir Pao Center for Cancer | And 6 more authors.
Cancer Letters | Year: 2010

Despite the demonstrated constitutive activation of NF-κB in nasopharyngeal carcinoma (NPC), the therapeutic potential of targeting this pathway has not been investigated. Here, we employed a small molecule inhibitor of NF-κB, DHMEQ (which mainly blocks nuclear translocation of activated NF-κB) and demonstrated significant inhibition of NPC cell proliferation, migration, invasion, as well as anchorage-independent growth. These antitumor effects were associated with induction of G2/M cell cycle arrest and apoptosis, and downregulation of NF-κB target genes (EGFR, cyclin D1 and survivin). This first demonstration of therapeutic benefits of NF-κB targeting in NPC implicates the importance of targeting this pathway in NPC. © 2009 Elsevier Ireland Ltd. All rights reserved.

Hu X.,Zhejiang University | Sui X.,Zhejiang University | Li L.,Sir Pao Center for Cancer | Li L.,Chinese University of Hong Kong | And 13 more authors.
Journal of Pathology | Year: 2013

Gastric and colorectal cancers are among the most common cancers worldwide and cause serious cancer mortality. Both epigenetic and genetic disruptions of tumour suppressor genes (TSGs) are frequently involved in their pathogenesis. Here, we studied the epigenetic and genetic alterations of a novel TSG-PCDH17 and its functions in the pathogenesis of these tumours. We found that PCDH17 was frequently silenced and methylated in almost all gastric and colorectal tumour cell lines as well as in ∼95% of primary tumours, but not in normal gastric and colonic mucosa. Moreover, its deletion was detected in only 18% of gastric and 12% of colorectal cancer tissues, suggesting that epigenetic and genetic inactivation of PCDH17 are both involved in gastric and colorectal tumourigenesis. PCDH17 protein expression was significantly correlated with low tumour stage and less lymph node metastasis of gastric and colorectal cancer patients, indicating its potential as a tumour marker. Restoring PCDH17 expression inhibited tumour cell growth in vitro and in vivo through promoting apoptosis, as evidenced by increased TUNEL staining and caspase-3 activation. Furthermore, PCDH17-induced autophagy, along with increased numbers of autophagic vacuoles and up-regulated autophagic proteins Atg-5, Atg-12 and LC3B II. Thus, PCDH17 acts as a tumour suppressor, exerting its anti-proliferative activity through inducing apoptosis and autophagy, and is frequently silenced in gastric and colorectal cancers. PCDH17 methylation is a tumour-specific event that could serve as an epigenetic biomarker for these tumours. Copyright © 2012 Pathological Society of Great Britain and Ireland.

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