He, Jun. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 136-156). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

大腸癌是全世界最常見的癌症之一，亦是一個癌症死亡率的首要原因。大腸癌患者約50%在病程中會出現轉移病灶。近十年來，雖然多種被批准用於臨床治療的新化療藥顯著提高了大腸癌的治療效果，但是轉移性大腸癌病人的預後仍然很差。隨著各種分子生物技術的進步，新的治療標靶可能在大腸癌細胞株中被發現，並得以在病人標本中驗證。 / 在本研究中，我們採用即時定量多聚酶鏈反應(qPCR)陣列分析，比較大腸癌細胞株和正常大腸細胞株基因表達譜，試圖識別潛在的新的治療標靶。結果提示，與正常大腸細胞株 CCD-18Co 比較，Jagged 2 (JAG2) 和 Frizzled-3 (FZD3)基因 在大腸癌細胞株 SW480 和 SW620 中表達升高。病人大腸癌組織的免疫組織化學染色 (IS) 檢查進一步證實了上述結果，大腸癌組織較其癌旁正常組織表達3.1倍JAG2和6.6倍FZD3蛋白。因此， 我們假設JAG2和FZD3在大腸癌的發生中起重要作用。 / 為了檢驗該假設的真偽，我們運用RNA 干擾的方法進行功能缺失研究。通過該方法，大腸癌細胞株中JAG2 信使RNA和蛋白均能夠被下調，但是FZD3蛋白卻沒有顯示降低。為了弄清JAG2基因的功能，我們進行了單層細胞劃痕傷口癒合試驗和Matrigel 侵襲試驗。結果提示，JAG2 基因下調顯著抑制大腸癌細胞遷移和侵襲的能力。 / 為了調查參與上述功能的機制，我們利用腫瘤轉移相關基因的qPCR陣列分析，試圖檢測出JAG2基因敲除後上調或下調表達的轉移相關基因。結果顯示組織蛋白酶K (CTSK)，一種溶酶體半胱氨酸蛋白酶，在JAG2基因沉默的大腸癌細胞株中表達下調。為了闡明CTSK 活性在大腸癌細胞株侵襲能力中起到的作用，我們採用CTSK抑制劑處理大腸癌細胞株HCT116和DLD-1，發現這兩種細胞株的侵襲能力分別下降了36%和59%。總之, 這些發現表明CTSK可能是JAG2的下游靶基因，活性CTSK可能參與了JAG2介導的大腸癌細胞株侵襲能力。 / 以前的研究表明p38 MAPK通路參與癌細胞遷和侵襲能力的調控。通過Western blot方法，磷酸化的p38和磷酸化的STAT3被發現在JAG2基因沉默的大腸癌細胞中表達降低。p38抑制劑處理的 HCT116和DLD-1細胞降低了侵襲能力下降，同時遷移能力也由於p38抑制劑的處理而降低，支持p38可調控癌細胞遷移和侵襲能力的事實。 / 總之，我們的結果顯示JAG2高表達通過啟動CTSK和p38 MAPK通路，可能促進大腸癌轉移。因此，JAG2可能成為轉移性大腸癌治療的潛在標靶。 / Colorectal cancer (CRC) is one of the most frequent cancers worldwide and is a leading cause of cancer mortality. Around 50% of patients with CRC will experience metastases. Although significant progress has been made in CRC treatment within the last decade with the approval of multiple new chemotherapeutic agents, the prognosis for patients with metastatic CRC remains poor. With the advancement of molecular techniques, novel therapeutic targets are able to be discovered in CRC cell lines and validated in patient samples. / Therefore in this project, I aim to identify potential novel therapeutic targets by comparing the gene expression profile of colon cancer cell lines and a normal colon cell line using quantitative polymerase chain reaction (qPCR) arrays. Results showed that Jagged 2 (JAG2) and Frizzled-3 (FZD3) were up-regulated in the CRC cell lines SW480 and SW620 as compared to the normal colon cell line CCD-18Co. Those results were further validated by immunohistochemical staining (IS), which detected up-regulated JAG2 (3.1-fold) and FZD3 (6.6-fold) proteins expression in CRC tissues as compared to adjacent normal tissues. Thus I hypothesized that JAG2 and FZD3 may play an important role in CRC carcinogenesis. / In order to study the roles of FZD3 and JAG2 in CRC, loss-of-function studies by RNA interference (RNAi) were carried out. While the expression of FZD3 protein failed to be down-regulated by RNAi, JAG2 expression was successfully knocked down in CRC cell lines at both the mRNA and protein levels. Functional analyses using the monolayer scratch wound-healing assay and Matrigel invasion assay showed that JAG2 knockdown significantly inhibited migration and invasion in CRC cell lines. / To investigate the mechanisms involved, a tumour metastasis qPCR array was used to examine the changes in the expression level of metastasis-related genes after JAG2 gene knockdown. Results showed that the expression of Cathepsin K (CTSK), a lysosomal cystein protease, was found to be down-regulated in CRC cell lines following JAG2 silencing. To demonstrate the importance of CTSK activity in CRC cell invasion, HCT116 and DLD-1 CRC cell lines were treated with a CTSK inhibitor and its effect were assessed by the Matrigel invasion assay. Results showed that CTSK inhibition led to a 36% and 59% reduction in number of invaded cells in HCT116 and DLD-1 cell lines, respectively. Taken together, these findings show that CTSK may be a downstream target of JAG2 and that active CTSK may involve in JAG2 mediated invasion in CRC cell lines. / Previous works by others have shown that the p38 MAPK pathway is involved in the regulation of migration and invasive activity of cancer cell lines. Using Western blot analysis, the expression of phosphorylated p38 MAPK and phosphorylated STAT3 were found to be down-regulated following JAG2 depletion in CRC cell lines. In support of a role for p38 MAPK in the regulation of cancer cell migration and invasive capability, treatment with a p38 MAPK inhibitor was found to reduce the percentage of invasive cells and distance moved by migratory cells in HCT116 and DLD-1 cell lines. / In conclusion, my results show that JAG2 over-expression in CRC may promote cancer cell migration and invasion through activation of CTSK and the p38 MAPK pathway. Therefore, JAG2 may be a potential therapeutic target for treatment of metastatic CRC. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / He, Wan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 164-207). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese. / Abstract in English --- p.i / Abstract in Chinese --- p.iv / Acknowledgements --- p.vi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Colorectal Cancer (CRC) --- p.1 / Chapter 1.1.1 --- Epidemiology and Incidence --- p.1 / Chapter 1.1.2 --- Histology --- p.2 / Chapter 1.1.3 --- Gender and Age --- p.4 / Chapter 1.1.4 --- Etiology of CRC --- p.4 / Chapter 1.1.4.1 --- Environment --- p.4 / Chapter 1.1.4.2 --- Hereditary Factors --- p.5 / Chapter 1.1.4.3 --- Dietary Factors --- p.6 / Chapter 1.1.4.4 --- Obesity --- p.6 / Chapter 1.1.4.5 --- Tobacco and alcoho --- p.7 / Chapter 1.1.4.6 --- Inflammatory bowel disease (IBC) --- p.7 / Chapter 1.1.5 --- Genetic Changes in CRC --- p.8 / Chapter 1.1.5.1 --- Chromosomal Aberration --- p.8 / Chapter 1.1.5.2 --- Tumor Suppressor Genes --- p.10 / Chapter 1.1.5.2.1 --- APC gene --- p.10 / Chapter 1.1.5.2.2 --- P53 gene --- p.11 / Chapter 1.1.5.2.3 --- SMAD4 gene --- p.11 / Chapter 1.1.5.3 --- Oncogenes --- p.12 / Chapter 1.1.5.3.1 --- Epidermal Growth Factor Receptor (EGFR) gene --- p.12 / Chapter 1.1.5.3.2 --- RAS gene and BRAF gene --- p.13 / Chapter 1.1.5.4 --- Proposed Two-hit Model for the Multistep Pathogenesis of CRC --- p.15 / Chapter 1.1.6 --- Clinical Presentation and Diagnosis --- p.16 / Chapter 1.1.7 --- Theatment --- p.16 / Chapter 1.1.7.1 --- Surgery --- p.16 / Chapter 1.1.7.2 --- Radiotherapy (RT) --- p.17 / Chapter 1.1.7.3 --- Concurrent Chemotherapy --- p.17 / Chapter 1.1.7.4 --- Target Therapy --- p.18 / Chapter 1.1.7.5 --- Colorectal Cancer Treatment by Stage --- p.19 / Chapter 1.1.7.6 --- Novel Strategies --- p.20 / Chapter 1.1.7.6.1 --- Epigenetic therapy --- p.20 / Chapter 1.1.7.6.2 --- Immunotherapy --- p.21 / Chapter 1.2 --- Pathways Involved in CRC Carcinogenesisand Progression --- p.22 / Chapter 1.2.1 --- Wnt Signaling Pathway --- p.22 / Chapter 1.2.2 --- Notch Signaling --- p.23 / Chapter 1.2.3 --- Nuclear Factor-kappa B (NF-κB) Signaling Pathway --- p.23 / Chapter 1.2.4 --- Phosphatidylinositol 3-kinase (PI3K) Signaling Pathway --- p.24 / Chapter 1.2.5 --- Crosstalk Among WNT, NOTCH, NF-κB and PI3K Signaling Pathway in CRC --- p.24 / Chapter 1.3 --- Hypothesis and Objectives of this Study --- p.28 / Chapter Chapter 2 --- Identification of Differentially Expressed Genes between Colorectal Cancer Cell Lines and A Normal Colon Cell Line --- p.29 / Chapter 2.1 --- Background --- p.29 / Chapter 2.2 --- Materials and Methods --- p.33 / Chapter 2.2.1 --- Cell Lines --- p.33 / Chapter 2.2.2 --- Identification of Differetially Expressed Genes by qPCR Arrays --- p.33 / Chapter 2.2.2.1 --- Total RNA Extraction --- p.33 / Chapter 2.2.2.2 --- RNA Quality Contol --- p.34 / Chapter 2.2.2.3 --- Reverse Transcription (RT) --- p.34 / Chapter 2.2.2.4 --- PCR Arrays --- p.34 / Chapter 2.3 --- Results --- p.36 / Chapter 2.3.1 --- Differentially Expressed Genes in WNT Signaling Pathway --- p.36 / Chapter 2.3.2 --- Differentially Expressed Genes in Notch Signaling Pathway --- p.40 / Chapter 2.3.3 --- Differentially Expressed Genes in NF-κB Signaling Pathway --- p.43 / Chapter 2.3.4 --- Differentially Expressed Genes in PI3K-AKT Signaling Pathway --- p.46 / Chapter 2.3.5 --- Choice of over-expressed genes for further validation and characterization --- p.49 / Chapter 2.4 --- Discussions --- p.53 / Chapter 2.4.1 --- WNT Signaling Pathway --- p.53 / Chapter 2.4.2 --- NOTCH Signaling Pathway --- p.54 / Chapter 2.4.3 --- NF-κB Signaling Pathway --- p.55 / Chapter 2.4.4 --- PI3K-AKT Signaling Pathway --- p.56 / Chapter 2.4.5 --- Choice of over-expressed genes for further validation and characterization --- p.56 / Chapter Chapter 3 --- JAG2, FZD3 and NOTCH4 Expression in Colorectal Cancer Cell Lines and Colorectal Cancer Tissues --- p.59 / Chapter 3.1 --- Background --- p.59 / Chapter 3.1.1 --- JAG2 Ligand --- p.59 / Chapter 3.1.2 --- FZD3 Receptor --- p.61 / Chapter 3.1.3 --- NOTCH4 Receptor --- p.62 / Chapter 3.2 --- Materials and Methods --- p.64 / Chapter 3.2.1 --- CRC Cell Lines --- p.65 / Chapter 3.2.2 --- CRC Tissues --- p.65 / Chapter 3.2.3 --- Quantitative RT-PCR --- p.66 / Chapter 3.2.4 --- Detection of JAG2, FZD3 and NOTCH4 Protein Expression in CRC Tissues by Immunohistochemical Staining (IS) --- p.67 / Chapter 3.2.5 --- Western Blot Assays --- p.68 / Chapter 3.2.5.1 --- Protein extraction --- p.68 / Chapter 3.2.5.2 --- SDS-PAGE gel electrophroresis --- p.68 / Chapter 3.2.5.3 --- Protein blotting --- p.68 / Chapter 3.2.6 --- Detection of JAG2 and FZD3 Protein Expression in CRC and Normal Colon Cell Lines by Western Blotting --- p.69 / Chapter 3.2.7 --- Statistical Analysis --- p.70 / Chapter 3.3 --- Results --- p.71 / Chapter 3.3.1 --- JAG2 and FZD3 but not NOTCH4 mRNA were Over -expressed in CRC Cell Lines --- p.71 / Chapter 3.3.2 --- Over-expression of JAG2 and FZD3 Proteins in CRC Tissues --- p.72 / Chapter 3.3.3 --- FZD3 Over-expression Correlated with Tumour-Node Metastasis (TNM) stages --- p.76 / Chapter 3.3.4 --- JAG2 and FZD3 Protein Expression in Colorectal Cancer and Normal Cell Lines --- p.77 / Chapter 3.4 --- Discussions --- p.78 / Chapter Chapter 4 --- Functional Analyses of JAG2 and FZD3 in CRC Cell Lines by RNA Interference --- p.81 / Chapter 4.1 --- Background --- p.81 / Chapter 4.2 --- Materials and Methods --- p.84 / Chapter 4.2.1 --- Transfection of siRNA into CRC Cell Lines --- p.84 / Chapter 4.2.2 --- Cell Proliferation Assay --- p.85 / Chapter 4.2.3 --- Monolayer Scratch Wound Healing Assay --- p.85 / Chapter 4.2.4 --- Matrigel Invasion Assay --- p.86 / Chapter 4.2.5 --- Statistical Analysis --- p.87 / Chapter 4.3 --- Results --- p.88 / Chapter 4.3.1 --- Knockdown of JAG2 and FZD3 Expression by RNA Interference --- p.88 / Chapter 4.3.2 --- Effect of JAG2 Knockdown on Migration of CRC Cell Lines --- p.91 / Chapter 4.3.3 --- JAG2 Knockdown by siRNA 2 Transfection Reduced Migratory Capability of HCT116, DLD-1and HT29 cell lines --- p.94 / Chapter 4.3.4 --- JAG2 Knockdown Impaired the Invasiveness of HCT116 and DLD-1 Cell Lines --- p.97 / Chapter 4.3.5 --- Decreased Migratory and Invasive Capabilities Induced by JAG2 Knockdown was not Due to Reduced Cell Proliferation --- p.100 / Chapter 4.4 --- Discussions --- p.102 / Chapter Chapter 5 --- NOTCH Pathway Inactivation by JAG2 Silencing Reduces Oncogenic Properties of HT29 but not HCT116 andDLD-1 CRC Cell Lines --- p.106 / Chapter 5.1 --- Background --- p.106 / Chapter 5.2 --- Materials and Methods --- p.109 / Chapter 5.2.1 --- CRC Cell lines --- p.109 / Chapter 5.2.2 --- Pharmacological Inhibition of NOTCH signaling by DAPT --- p.109 / Chapter 5.2.3 --- Combination of DAPT Treatment and JAG2 Silencing by siRNA --- p.109 / Chapter 5.2.4 --- Western Blotting --- p.109 / Chapter 5.2.5 --- Cell Proliferation Assay (MTS Assay) --- p.110 / Chapter 5.2.6 --- Monolayer Scratch Wound Healing Assay --- p.110 / Chapter 5.2.7 --- Matrigel Invasion Assay --- p.111 / Chapter 5.2.8 --- Statistical Analysis --- p.111 / Chapter 5.3 --- Results --- p.112 / Chapter 5.3.1 --- JAG2 Silencing Down-regulates Notch Pathway Signaling in CRC Cell Lines --- p.112 / Chapter 5.3.2 --- Inhibition of NOTCH Signaling by DAPT Treatment in CRC Cell Lines --- p.112 / Chapter 5.3.3 --- NOTCH Inhibition Does not Significantly Affect Cell Proliferation in CRC Cell Lines --- p.114 / Chapter 5.3.4 --- Suppression of NOTCH Signaling by DAPT Inhibits Migration in HT29 but not in HCT116 and DLD-1 CRC Cell Lines --- p.115 / Chapter 5.3.5 --- Suppression of NOTCH Signaling by DAPT does not Significantly Affect Invasiveness of HCT116 and DLD-1 CRC Cell Lines --- p.117 / Chapter 5.4 --- Discussions --- p.118 / Chapter Chapter 6 --- JAG2 Knockdown Inhibits Invasion in CRC Cell Lines through Inactivation of Cathepsin K --- p.121 / Chapter 6.1 --- Background --- p.121 / Chapter 6.2 --- Materials and Methods --- p.123 / Chapter 6.2.1 --- Human Tumour Metastasis RT2 Profiler[superscript TM] PCR Array --- p.123 / Chapter 6.2.2 --- Measurement of CTSK Gene expression level by Quantitative Real-Time PCR --- p.123 / Chapter 6.2.3 --- Immunohistochemical Staining (IS) of CTSK in CRC Tissues --- p.124 / Chapter 6.2.4 --- Pharmacological Inhibitior of CTSK in CRC Cell Lines --- p.124 / Chapter 6.2.5 --- Inhibition of CTSK in CRC Cell Lines for Migration Study --- p.124 / Chapter 6.2.6 --- Inhibition of CTSK in CRC Cell Lines for Invasion Study --- p.125 / Chapter 6.2.7 --- Western Blotting --- p.125 / Chapter 6.2.8 --- Statistical Analysis --- p.125 / Chapter 6.3 --- Results --- p.126 / Chapter 6.3.1 --- Identification of Metastasis Related Genes Which were Down-regulated by JAG2 Knockdown in HCT116 Cells --- p.126 / Chapter 6.3.2 --- Validation of Down-regulation of CTSK Gene by JAG2 Knockdown in HCT116 Cell Line by qRT-PCR --- p.126 / Chapter 6.3.3 --- JAG2 Knockdown Reduced Expression of Active CTSK Protein in CRC Cell Lines --- p.128 / Chapter 6.3.4 --- CTSK Protein Expression in CRC Tissue Samples --- p.130 / Chapter 6.3.5 --- Pharmacological Inhibition of CTSK Suppressed Invasiveness of CRC Cell Lines --- p.131 / Chapter 6.3.6 --- Pharmacological Inhibition of CTSK did not Affect Migration of CRC Cell Lines --- p.132 / Chapter 6.4 --- Discussions --- p.133 / Chapter Chapter 7 --- Depletion of JAG2 Inhibits Migration and Invasion in CRC Cell Lines through Inactivation of p38 MAPK/HSP27 Pathway --- p.137 / Chapter 7.1 --- Background --- p.137 / Chapter 7.2 --- Materials and Methods --- p.140 / Chapter 7.2.1 --- Pharmocological Inhibition of p38 MAPK Phosphorylation CRC Cell Lines --- p.140 / Chapter 7.2.2 --- Inhibition of p38 MAPK Phosphorylation for Migration Study in CRC Cell Lines --- p.140 / Chapter 7.2.3 --- Inhibition of p38 MAPK Phosphorylation for Invasion Study in CRC Cell Lines --- p.140 / Chapter 7.2.4 --- Knockdown of STAT3 by RNA interference --- p.141 / Chapter 7.2.5 --- Knockdown of STAT3 for Migration Study in CRC Cell Lines --- p.141 / Chapter 7.2.6 --- Knockdown of STAT3 for Invasion Study in CRC Cell Lines --- p.141 / Chapter 7.2.7 --- Western Blotting --- p.141 / Chapter 7.2.8 --- Statistical Analysis --- p.142 / Chapter 7.3 --- Results --- p.143 / Chapter 7.3.1 --- JAG2 Knockdown Inhibits p38 MAPK / HSP27 Pathway in CRC Cell Lines --- p.143 / Chapter 7.3.2 --- Inhibition of p38 MAPK / HSP27 Signaling Pathway Down-regulated Invasive Capability of CRC Cell Line --- p.145 / Chapter 7.3.3 --- Inhibition of p38 MAPK / HSP27 Signaling Pathway Down-regulated Migration of CRC Cell lines --- p.147 / Chapter 7.3.4 --- JAG2 Knockdown Inactivated p38 MAPK / HSP27 Pathway Independently of NOTCH Pathway in CRC Cell Lines --- p.149 / Chapter 7.3.5 --- JAG2 Knockdown Inhibits STAT3 Activation in CRC Cell Lines --- p.151 / Chapter 7.3.6 --- STAT3 Silencing Reduced Invasive Capability in CRC Cell Lines --- p.152 / Chapter 7.3.7 --- STAT3 Silencing Reduced Migratory Capability in CRC Cell Lines --- p.154 / Chapter 7.3.8 --- Inhibition of p38 MAPK Activity Suppressed STAT3 Activation in HCT116 Cells --- p.156 / Chapter 7.4 --- Discussions --- p.157 / Chapter Chapter 8 --- Conclusions and Future Works --- p.161 / Chapter 8.1 --- Conclusions --- p.161 / Chapter 8.2 --- Future work --- p.163 / References --- p.164 / Chapter Appendix 1 --- List of Figures and Tables --- p.208 / Chapter Appendix 2 --- Abbrevations used in this thesis --- p.212

published_or_final_version / Medicine / Master / Master of Medical Sciences

published_or_final_version / Diagnostic Radiology / Doctoral / Doctor of Philosophy

Thesis (M.D.)--University of Adelaide, Dept. of Surgery, 1999. / Includes bibliographical references (leaves 249-291).

Thesis (Ph. D.)--Ohio State University, 2007.

Le cancer colo-rectal est un problème de santé publique majeur dans les pays développés. Le cancer du rectum est défini comme une marge distale de la tumeur à moins de 15 cm de la marge anale. Sa prise en charge optimale impose une discussion entre une chirurgie mutilante emportant les sphincters ou une chirurgie conservatrice laissant en place l'appareil sphinctérien et évitant l'incontinence et la colostomie. L’Imagerie par résonance magnétique (IRM) est l’examen de référence pour le diagnostic de la tumeur initiale. Dans projet, nous avons utilisé des outils IRM modernes comme la volumétrie et l’imagerie de diffusion dans l’évaluation thérapeutique des cancers du rectum après chimioradiothérapie.Nous avons ainsi montré que la variation de volume tumoral au cours du traitement du cancer du rectum était associée à une survie sans récidive à 5 ans : les patients dont le volume tumoral diminuait d'au moins 70% au cours du traitement néoadjuvant avaient une survie à 5 ans sans récidive et un grade de régression histologique significativement plus élevée que chez les patients dont le volume diminuait de moins de 70%. En utilisant la même technique de volumétrie tumorale tridimensionnelle au cours d'un essai thérapeutique, nous avons également montré pour la première fois que la variation précoce de volume tumoral du rectum au cours du traitement néoadjuvant par chimiothérapie seule pouvait prédire le succès du traitement ultérieur par radio-chimiothérapie puis chirurgie. L'étude de la variation précoce de volume tumoral est actuellement utilisée dans un essai randomisé prospectif multicentrique dans lequel la variation de volume tumoral du rectum après radio-chimiothérapie néoadjuvante chez des patients avec tumeur avancée (T3c, T4) est le déterminant de la poursuite d'un traitement radio-chimiothérapique néoadjuvant ou le traitement chirurgical radical (essai GRECCAR4, ClinicalTrials.gov NCT01333709). Nous nous sommes ensuite intéressés à l’imagerie de diffusion et en particulier l’IVIM marqueur prédictif de réponse thérapeutique. Dans cette étude, la diffusion pure permettait d’obtenir des résultats prometteurs pour l’évaluation de la réponse au traitement néoadjuvant. Finalement, nous présenterons les perspectives de recherche concernant un type particulier de réponse, les réponses colloïdes. / Colo-Rectal Cancer is the third most commonly diagnosed cancer in males and the second in females. Around 30% of all colorectal cancers are diagnosed in the rectum. Despite the major improvements that have been made management of rectal cancer still remains a challenge. Chemoradiotherapy (CRT) followed by surgery has been widely adopted for the management of locally advanced rectal cancers because this approach increases the probability of anal sphincter preservation, decreases the local recurrence rate and decreased the risk of colostomy. As we enter the era of personalized medicine with therapies stratified according to the risk of local or distant recurrence, imaging has become an essential tool in the preoperative decision making, to avoid both under- and overtreatment. Magnetic Resonance (MR) imaging is now an essential tool to enable the oncology team to make appropriate treatment decisions. First, we demonstrated that tumor shrinkage after preoperative chemotherapy–radiation therapy was associated with good response. Second, we demonstrated that early tumor volume decrease after induction chemotherapy before chemoradiotherapy was as well associated with good patient prognosis. Third, we demonstrated the added value of DW MR imaging for predicting tumor response using IVIM, a more sophisticated diffusion analytic approaches, which allows quantitative parameters that reflect tissue microcapillary perfusion and tissue diffusivity to be derived. In this study we demonstrated that true diffusion was associated with regression grade on pathology. Finally, we will present our perspectives especially in tumor response evaluation in patient with colloidal response.

Colorectal cancer is second only to lung cancer as a leading cause of internal cancer death. Individuals over 65 years of age are most at risk yet least likely to engage in screening for colorectal cancer. The purpose of this descriptive-correlational study using a modified Pender Health Promotion Model was to identify motivations of elderly individuals to engage in health protective behavior. A convenience sample of 90 subjects answered a four-part motivations questionnaire in which three subscales--early detection, powerful others, and chance--met reliability standards (alpha >.70). Chance was significantly related to compliance (r = -.28; p =.003); Hemoccult compliers believed less in chance and powerful others than did non-compliers (p =.005;.002). The 88 percent who performed a Hemoccult stool test as a screening method for early detection of colorectal cancer demonstrated that these elders willingly engaged in health protective behavior and supported the nurses' role in promoting primary prevention in elderly clients.

Nous avons analysé la relation entre le risque de cancer colorectal et la consommation de viande et de poisson dans la population qui participe dans l'Etude Prospective Européenne sur le Cancer et la Nutrition. Il s'agit d'une étude sur plus de 400 000 sujets volontaires de dix pays européens. Le risque de cancer colorectal apparaît lié à un niveau de consommation élevé de viande rouge. Le hazard ratio associé à une consommation supérieure à 160 grammes par jour par rapport à une consommation inférieure à 20 grammes par jour est de 1.35 (95% IC=0.96-1.88). La consommation élevée de poisson semble diminuer le risque de cancer colorectal. Le hazard ratio pour une consommation de poisson supérieure à 80 grammes par jour par rapport à celle de moins de 10 grammes par jour est de 0.69 (IC=0.54-0.88). La consommation de volailles n'a pas d'incidence sur le risque de cancer colorectal. Nous avons intégré par méta-analyse nos résultats avec ceux des études prospectives publiées entre 1990 et juin 2006. D'après 14 études, le risque relatif moyen associé aux niveaux de consommation de viande rouge les plus hauts par rapport aux niveaux les plus bas est de 1.34 (95% CI=1.09-1.21). En ce qui concerne les niveaux de consommation de poisson les plus hauts par rapport aux niveaux les plus bas (treize études), le risque relatif moyen est de 0.87 (95%CI=0.78-0.97). Nos résultats montrent qu'une diminution des apports de viande rouge parmi les gros consommateurs devrait conduire à une diminution du risque de cancer colorectal pour cette population. La consommation de fibre alimentaire et de poisson en grosses quantités semble diminuer le risque, mais cette relation doit être confirmée par d'autres études.

Colorectal neoplasia (CRN) continues to be a leading cause of morbidity and mortality in the developed world and with westernisation, similar trends are now emerging in the developing world. Although secondary prevention through screening programmes has reduced mortality, uptake remains poor due to the invasive nature of colonoscopy, which also exerts increased costs to the health care system. Primary prevention remains the ultimate aim to reduce the morbidity and mortality associated with CRN. In this regard, chemoprevention strategies through regular use of aspirin and other NSAIDS have showed great promise but the associated significant side-effects of these drugs has prevented their routine clinical application for this purpose. Hence there is an urgent need for the identification of safer alternatives for primary prevention of CRN. In parallel to this search, better understanding of the molecular pathogenesis of CRN to identify biomarkers that aid in stratification of at risk individuals would also help. In this regard, the role of chronic inflammation and the influence of host genetics in the pathogenesis of CRN has been the focus of extensive research in recent years. However there is a lack of studies which have investigated these associations in an exclusively screened population, which confers some advantages for this type of investigation. Firstly, most of the screened subjects are relatively healthy, asymptomatic and with no significant co-morbidities, the factors which could otherwise influence the levels of inflammatory markers. Secondly, the screened population is in the 50 to74 year age group which represents the group with a high prevalence of CRN and hence increasing the possibility of finding associations which would be more relevant and generalisable. Thirdly, the selected controls match the cases in all important respects, apart from having CRN, thus increasing the validity of the findings in this population. The Grampian region was one of the first in the UK to participate in the National Colorectal Cancer Screening Programme and this resource gave the ideal opportunity to conduct research involving an exclusively screened population. Utilising this cohort, the current thesis addressed three important aspects of the association between inflammation and CRN. Firstly the investigation of the association of inflammatory genotype, inflammatory phenotype and CRN risk. Secondly the impact of environmental factors, specifically dietary antiinflammatory salicylic acid intakes on CRN risk. And finally assessing if inflammation, and hence in the long term risk of CRN, could be attenuated through a comprehensive anti-inflammatory dietary supplementation in the form of a randomised dietary intervention clinical trial. The study of the association of polymorphisms in key inflammatory genes (IL1B- 31, IL8-251, IL6-174, TNFα-308, IL10-1082, IL10-592, PTGS2-765, and IL1RN VNTR) and CRN risk showed some significant findings. A novel finding was that the homozygous IL1B-31C*C genotype was associated with statistically significant increased risk of CRN, OR 1.63 (95% CI 1.06-2.50) whilst the IL8-251 A*A genotype increased the propensity of having high risk lesions by two-fold (OR 2.04; 95% CI 1.02-4.07). The study of circulating inflammatory marker levels in subjects in whom the CRN was in-situ showed that increased CRP levels were associated with increased risk of CRN, OR 1.55 (95% CI 1.00-2.39). Increased levels of IL8 were associated with increased risk of having a high risk lesion, OR 2.57 (95% CI 1.03-6.44). In a sub group of subjects, it was observed that levels IL8 and CRP decreased following polypectomy (mean IL8 20.3 pg/ml to 14.9 pg/ml, p=0.05 and mean CRP 5.99 mg/l to 3.82 mg/l, p=0.07) raising an important question regarding the sequence of the inflammation-neoplasia cascade, “Is inflammation the cause or the effect of neoplasia?” The study of the association of dietary salicylic acid (SA) and CRN using the newly constructed SA database showed that high levels of total SA (aspirin and dietary SA) intakes were associated with a 75% and moderate levels with a 67% decreased risk of CRN. But dietary SA on its own showed no significant effect on CRN risk probably because of low intake levels in the current cohort. Applying the SA database to populations with higher dietary SA intake would help to further explore its association with CRN risk. The randomised clinical trial examining the effect of a combined antiinflammatory dietary supplement (curcumin, omega-3 PUFA and polyphenols rich fruit smoothie) on markers of inflammation in subjects who had adenomatous colorectal polyps removed showed that the inflammatory marker levels in the control group who just continued their habitual diet remained stable without any statistically significant changes at 6 weeks compared to the baseline. Whereas following 6 weeks of dietary intervention, there was marginally significant increase in IL8 and IL1B levels. One of the possible mechanisms for increase in pro-inflammatory marker levels in the intervention group was the weight gain seen in the intervention group. In the intervention group, the post-intervention mean weight (86.80kgs) was significantly higher than the pre-intervention mean weight (85.38 kgs). In summary, the findings from these investigations suggest that a proinflammatory genotype (IL1B-31C*C and IL8-251 A*A) and elevated circulating inflammatory marker levels (CRP and IL8) are associated with increased risk of CRN. And along with the findings that regular NSAID use and total dietary SA are associated with decreased risk of CRN, our data point to inflammation as an underlying pathogenetic mechanism in CRN. The pilot clinical trial has demonstrated that a clinical trial with combined dietary supplementation is feasible, but challenging. The anti-inflammatory dietary intervention strategy employed to reduce the inflammatory markers did not achieve the desired effect and hence more research is required to establish the ideal delivery strategy of the anti-inflammatory dietary agents. Once this is established, dietary chemoprevention of CRN as a safe alternative should be a realistic achievable goal in the future.