published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Medicine / Master / Doctor of Medicine

published_or_final_version / abstract / Medicine / Master / Doctor of Medicine

Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China. Deletion of genomic DNA, which occurs during the complex pathogenesis process for NPC, represents a pivotal mechanism in the inactivation of tumor suppressor genes (TSGs). In many circumstances, loss of TSGs can be detected as diagnostic and prognostic markers in cancer treatment. It is found that the short arm of chromosome 3 (3p) is frequently deleted in NPC, with two most frequently minimally deleted regions at 3p21.1-21.2 and 3p25.2-26.1. Recently, our research group and others have focused on the identification and characterization of novel TSGs in the 3p deleted region. Three new tumor suppressor genes, CACNA2D3, RBMS3 and CHL1 were identified by our group. In this thesis, I found thatRBMS3at3p24was down-regulated in 3/3 NPC cell lines and 13/15 (86.7%) primary NPC tissues, compared with corresponding non-tumor tissues. Functional study demonstrated that RBMS3hadstrong tumor suppressive function in NPC cells, including inhibiting the cell growth rate, colony formation in soft-agar and tumor formation in nude mice. Moreover, the tumor suppressive mechanism of RBMS3was involved with the cell cycle arrest at the G1/S checkpoint.RBMS3 also had a pro-apoptotic role in a mitochondrial-dependent manner. Finally, RBMS3 could inhibit microvessel formation. Located at the important tumor suppressor locus 3p26.1, CHL1encodes a one-pass trans-membrane cell adhesion molecule (CAM). I identified CHL1as a tumor suppressor gene in nasopharyngeal carcinoma through expression profiling and epigenetic characterization. In this study, down-regulation of CHL1 was detected in 3/3of NPC cell lines and 12/15 (80.0%) of NPC tissues. Expression of CHL1could be reversed by pharmacological demethylation with 5-aza, indicating that promoter methylation might play an important role inCHL1down-regulation. Functional study showed that ectopic expression of CHL1 in NPC cells could dramatically inhibit clonogenicity and cell motility, possibly through cell cycle arrest. Further study found that CHL1 was able to induce mesenchymal-epithelial transition (MET), a key event to prevent tumor invasion and metastasis, by up-regulating epithelial markers and down-regulating mesenchymal markers. In addition, CHL1could inactivate RhoA/Rac1/Cdc42 signaling pathway to decrease the formation of stress fiber, lamellipodia and filopodia. In conclusion, these findings demonstrate thatCHL1is an important tumor suppressor gene in NPC. Later, I identified CHL1 could co-localize with integrin-beta1, an adhesion molecular, and expression of CHL1 was positively correlated with integrin-beta1. Moreover, CHL1 could interact with integrin-beta1 by using pull-down assay. Also, the tumor suppressor merlin could interact with CHL1. However, when CHL1 is lost, integrin beta1-AKT pathway would be activated and merlin will be phosphorylated and become inactivated, then it could not function as a tumor suppressor anymore. In this thesis, I summarize my recent work on two TSGs at 3p, RBMS3and CHL1, in the development and progression of NPC. Better understanding of TSGs at 3p will greatly improve our knowledge on pathogenesis of NPC, diagnosis and treatment. / published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy

Thesis (M. Ed.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 103-118).

published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Anatomy / Master / Master of Research in Medicine

published_or_final_version / Clinical Oncology / Master / Master of Philosophy

Nasopharyngeal carcinoma (NPC) is an endemic malignant disease in Southern China. Intensity-modulated radiotherapy (IMRT) has been employed as a standard treatment for NPC because it delivers highly conformal dose distribution to target volumes and spares organs at risk (OARs). The success of radiotherapy depends on the accurate delivery of the planned doses throughout the treatment. This can be achieved with the help of advanced image-guided adaptive radiotherapy (IGART) such as kilovoltage (kV) cone beam computed tomography (CBCT) which can reduce the geometric setup uncertainty, monitor the intra-course anatomic and dosimetric changes and adjust the treatment plan. The aim of this thesis is to study the role of repeat imaging for NPC and the radiation dose from CBCT to patients. The objectives of this thesis are to evaluate the volumetric and dosimetric changes during a course of IMRT for loco-regionally advanced NPC patients with the contribution of repeat computed tomography (CT) and magnetic resonance imaging (MRI) scans; to quantify the absorbed dose, effective dose and the estimation of the additional risk of inducing fatal cancers from CBCT for NPC patients undergoing IMRT; and to compare the image quality of different head protocols. Nineteen loco-regionally advanced NPC patients treated with IMRT were recruited prospectively. Repeat CT and MRI were acquired at 30 and 50 Gy intervals. Recontouring of target volumes and OARs was based on the fused CT-MRI images. Hybrid plans with recontouring were generated. The volumetric and dosimetric changes were assessed by comparing the hybrid plans with the original plan. There was volume reduction of target volumes and parotid glands over the course of IMRT. Relative to the original plan, the hybrid plans demonstrated significantly higher dose to the target volumes with greater dose inhomogeneity, higher maximum doses to the spinal cord and brainstem, and higher medium doses to the parotid glands. The image quality and dosimetry on the Varian CBCT system between software Versions 1.4.13 (“new” protocol) and 1.4.11 (“old” protocol) were studied. A calibrated Farmer-type ionization chamber and a standard cylindrical Perspex CT dosimetry head phantom were used to measure the weighted CBCT dose index (CBCTDIw) of the Varian CBCT system. The absorbed dose of different organs was measured in a female anthropomorphic phantom with thermoluminescent dosimeters (TLD) and the total effective dose was estimated according to ICRP Publication 103. The dosimetry and image quality were studied for head-and-neck region and comparison was made between the new and old protocols. The values of the CBCTDIw, absorbed dose, effective dose of the new head protocol were much lower than the old head protocol in each imaging group. The additional fatal cancer risk from daily CBCT might be up to 1.6%. In conclusion, replanning with repeat imaging at 30 Gy is essential to keep a satisfactory dose to the target volumes and avoid overdosing the OARs for NPC patients. The new Varian CBCT provides volumetric information for image guidance with acceptable image quality and lower radiation dose. This CBCT gives a better standard for NPC patient daily setup verification. / published_or_final_version / Clinical Oncology / Doctoral / Doctor of Philosophy