Chen, Shih-Hsin; (2019) Multiple-Parametric Imaging of Tumour Angiogenesis in Colorectal Cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Angiogenesis is an important aspect in tumour growth. The effectiveness of anti-angiogenic drugs in metastatic colorectal cancer implies importance of this hallmark in the third most common cancer type worldwide. Exosomes, cell-secreted vesicles of approximately 50-150 nm consisting of proteins and microRNAs that are known to affect the behaviours of recipient cells, may be important for tumour cells modulating their environment such as angiogenesis in response to hypoxia. In this study, FDG-PET, CT perfusion and texture analysis performed on the FDG-PET/CT and CT perfusion images were analysed in a cohort of prospectively-recruited colorectal cancer patients. The predictive value of these image parameters on patients’ outcome was tested. Correlation between image parameters and angiogenesis markers as demonstrated by immunohistochemical staining on available surgical specimens was also sought. The relationship between exosomal proteins related to hypoxia and proliferation isolated from patient’s serum and these parameters was also put to the test. 364 patients were recruited into this ethically approved study from 2007 to mid-2017. CT perfusion was successfully performed in 293 patients. Histology specimen were collected in 153 patients. The follow-up time was 0.3-116 months (median: 33.4 months), during which time there were 96 deaths. CT perfusion parameters were not predictive of survival. On the FDG-PET/CT images, those with higher TLG had worse survival in patients with colon cancer. Kurtosis of the finely and intermediately-filtered CT images were stable prognosticators in addition to stage when dividing the patients into testing and validating groups in a 2:1 ratio. On the histology specimens, CD105 was positively correlated with VEGF, while negatively correlated with HIF-1α. VEGF expression was found to be positively correlated with mean transit time and negatively correlated with mean slope of increase from the CT perfusion scans. We found P4HA1 in the exosomes increased after hypoxia treatment in cell lines. In exosomes isolated from 54 colorectal cancer patients, we found patients with higher P4HA1 had higher EGFR. The exosomal EGFR signal intensity was negatively correlated with mean slope of increase from CT perfusion scans. However, no difference was found between those with metastatic or localized disease, nor did the exosomal protein expressions affect patient survival. In summary, a prognosticator, kurtosis of CT images, was found in addition to the clinical stage. Mean slope of increase from the CT perfusion was found to be negatively correlated with VEGF expression on histology specimens and exosomal EGFR intensity. Angiogenesis could be reflected on CT perfusion confirmed by relevant protein expressions in the tumour tissue and exosomes, but not necessarily affect patients’ outcome.

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