Browsing by Author "Bathe, Oliver"

Now showing 1 - 9 of 9
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    Examining the Functional Consequences of Tumor Endothelial Marker 8 (TEM8) Expression in Human Breast Cancer Cells
    (2014-04-17) Sampson, Elliot; Bathe, Oliver
    Tumor Endothelial Marker 8 (TEM8) is a type-1 transmembrane protein overexpressed in tumor associated endothelial cells. Preliminary data from our lab found markedly elevated levels of TEM8 in invasive human breast cancer cell lines of the basal subtype, and reduced TEM8 expression in non-invasive breast cancer cells of the luminal subtype. The functional significance of TEM8 expression in a human breast cancer context is unknown. This thesis explored the consequences of overexpression of TEM8 in non-invasive breast cancer cell lines. MCF7, HTB20, and SKBR3 cells constitutively express low levels of TEM8. The cell lines were infected with lentivirus encoding pLentiTEM8 or control pLentiLacZ. Functional alterations in tumor cell behavior (i.e. viability, apoptosis, adhesion, migration, and invasion) were investigated. NOD-SCID mice were used to evaluate changes in tumor kinetics. In silico data provided by MediSapiens™ was used to assess the prognostic significance of TEM8. The results of this thesis revealed that TEM8 is not sufficient to alter the behavior of non-invasive breast cancer cells to a more malignant phenotype. In vivo studies revealed overexpression of TEM8 does not enhance tumor growth in female NOD-SCID mice. Knocking out host derived TEM8 in MMTV-neu mice had no impact on tumor growth and mortality. In silico data delineate a relationship between TEM8 expression and loco-regional lymphatic spread. The significance of this thesis is that TEM8 alone is not sufficient to cause alterations in the biological behavior of MCF7, HTB20, and SKBR3; however, it may predict loco-regional spread of breast cancer to lymph nodes.
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    Fatty acid synthesis in colorectal cancer: characterization of lipid metabolism in serum, tumour, and normal host tissues
    (2015-05-01) Mackay, Emily; Bathe, Oliver; Weljie, Aalim
    Reprogrammed energy metabolism is now listed as one of the central hallmarks of cancer cells. Aberrant fatty acid metabolism contributes to tumourigenesis through provision of substrates for membrane synthesis, signalling molecules, and synthesis of complex lipids. In this thesis, the role of fatty acid metabolism is explored in the context of colorectal cancer. Metabolomics techniques were employed to characterize fatty acid metabolites in serum, and lipogenic gene expression was quantified in tumour and normal tissues to investigate host response to cancer. Fatty acid metabolite abundance was increased in the serum of individuals with colorectal cancer, and a growth factor signalling axis and lipogenic transcription factor upstream of the endogenous fatty acid synthesis pathway were increased in colorectal liver metastases. It was concluded that liver metastases have an effect on growth factor production in the hepatic microenvironment, leading to increased signalling through a pathway that activates the lipogenic transcription factor that regulates fatty acid synthesis.
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    Metabolomic Biomarkers of Response to Systemic Therapy in Colorectal Cancer
    (2021-07-07) Rattner, Jodi Ilana; Bathe, Oliver; Vogel, Hans; Kopciuk, Karen; Tang, Patricia
    Colorectal Cancer (CRC) is the 2nd leading cause of cancer death in North America. Besides surgery and radiation, chemotherapy administration is one of the mainstay treatment options used to improve CRC prognosis, and ultimately patient outcomes. Chemotherapies are selected empirically by oncologists, and only a fraction of these patients will experience the benefit of these therapies. Response is assessed through radiographic imaging (CT/MRI scans). However, a myriad of challenges, including time-delays and obstacles in measuring response (such as in molecularly targeted agents), means a new method of assessment is required to prevent unnecessary administration of unbeneficial therapies or undue accumulation of severe toxicities. This work describes the identification and development of metabolomic biomarkers that distinguishes the biological changes associated with the development of cancer progression, hypertension, and fatigue. Metabolomic profiling, a method in which the measurement of biological systems by describing the changes in molecular components constituting the metabolic state, was used. The metabolome is known to change rapidly within pathophysiological contexts and was chosen for its close relationship to phenotype, and its capacity to detect subtle changes in metabolite concentrations. Chapter 2 describes the protocol methodology using gas chromatography-mass spectrometry (GC-MS) and multivariate statistical analysis used in the development of plasma biomarkers. In Chapter 3, a large study using serial plasma samples from 220 CRC patients from an international clinical trial by GC-MS, which resulted in the development of a metabolomic biomarker distinguishing progression from partial response within one week of chemotherapy administration. In Chapter 4, using 70 CRC patients treated with cetuximab and brivanib, we aimed to establish a signature identifying differences in metabolomic changes signifying the development of hypertension within 12 weeks of treatment initiation. Chapter 5 was dedicated to the exploration of metabolomic changes accompanying the complexities associated with severe fatigue in 72 CRC patients. While the concepts presented in this work are not validated, the novel approach and careful considerations taken provide a proof of concept that have the possibility of substantiating and improving upon current clinical methods used. Therefore, this thesis is focused on the understanding of metabolomic perturbations of systemic therapy in CRC and the adaption of this knowledge for the development of signatures of progression for the use of clinically viable biomarkers for therapeutic assessment.
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    Rupture and intra-peritoneal bleeding of a hepatocellular carcinoma after a transarterial chemoembolization procedure: a case report
    (BioMed Central, 2009-01-20) Reso, Artan; Ball, Chad G.; Sutherland, Francis R.; Bathe, Oliver; Dixon, Elijah
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    Spiked-in Data Set for BMC Notes paper
    (2016) Kopciuk, Karen; Bathe, Oliver; McConnell, Yarrow; Welje, Aalim; de Leon, Alexander
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    Steps involved in designing and creating the spiked-in data set
    (2016) Kopciuk, Karen; McConnell, Yarrow; Bathe, Oliver; Weljie, Aalim
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    Targeted Serum Metabolomics for Noninvasive Detection of Colorectal Neoplasia
    (2023-08) Fitzgerald, Liam Warren; Bathe, Oliver; Orton, Dennis; Kopciuk, Karen; Vogel, Hans
    Background: Early detection of colorectal cancer (CRC) and its precursor lesions improves CRC-related mortality and reduces disease incidence. However, due to limitations of currently available screening modalities, patient adherence to screening is low. A reliable and inexpensive blood test represents a promising solution to this problem. Our group has previously demonstrated that there are distinct metabolic perturbations in CRC and adenomatous polyps which are measurable in the blood. However, a targeted metabolomic approach is needed to uncover reliable meta-biomarkers for CRC, adenomatous polyps, and serrated polyps. Methods: A targeted metabolomic assay (Biocrates MxP® Quant 500) was used to analyze our discovery set of sera from patients with CRC of all stage (N=111), adenoma (N=63), sessile serrated adenoma (SSA; N=62), and age- and sex-matched disease-free controls (DFC; N=154). Orthogonal partial least squares discriminant analysis (OPLS-DA) and machine learning (ML) were used to derive signatures comprised of metabolite concentration ratios which discriminate between CRC, adenoma, SSA, and DFCs. A large, representative validation cohort (N=838) was also analyzed to test our meta-biomarkers. Results: Two signatures for CRC were derived from OPLS-DA and ML and comprised of 21 and 16 metabolite ratios, respectively. OPLS-DA signatures for adenoma and SSA were comprised of 23 and 56 metabolite ratios, respectively. All models performed well based on 7-fold internal cross-validation, with receiver operating characteristic (ROC) analysis demonstrating areas under the curve (AUC) greater than 0.85. Importantly, external validation confirmed the reliability of our meta-biomarkers, with sensitivities as high as 92-100% for CRC and 80-85% for adenoma and SSA being possible. Conclusion: Our meta-biomarkers discovered using targeted metabolomics demonstrated excellent performance based on internal and external validation. Of significance, our signatures exhibit superior sensitivity compared to other readily available screening modalities such as stool tests.
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    The Effects of Diet, Body Composition and Exercise on The Serum Metabolome in Health and Disease
    (2017) Palmnäs, Marie; Vogel, Hans; Bathe, Oliver; Shearer, Jane; Csizmadi, Ilona
    The serum metabolite profile reflects a great variety of factors including age, gender, diet, exercise, gut microbial metabolism and the presence of disease. Importantly, changes in the serum metabolome may appear prior to the clinical manifestation of disease, provide insight into underlying biological mechanisms and be predictive of disease progression and/or amelioration. Using an animal model and human participants, the serum metabolome of obesity was studied in relations to diet and physical activity. In brief, obese rats consuming coffee had a favorable body composition, lower liver triglycerides and decreased serum concentrations of branched-chain amino acids, which are thought to cause diabetes when present at higher concentrations, compared to controls. In contrast, aspartame consuming rats showed impairments in glucoregulation. Our findings suggested that this might have been a result of aspartame causing an increase in the proportion of gut bacteria that produce propionate, a metabolite known to stimulate hepatic gluconeogenesis. In human subjects, obesity and metabolic syndrome risk factors were associated with lower concentrations of the sphingolipid precursors serine and glycine. Higher activity energy expenditure and physical activity levels showed the opposite association. Physical activity may thus improve on insulin sensitivity by reducing de novo synthesis of sphingolipids and their subsequent accumulation in insulin-sensitive tissues. Exercise also associated with improvements in body weight, lean mass, physical performance and symptom severity, following cancer treatment in head and neck cancer patients. However, none of these factors correlated with their 2-year survival. Instead, the baseline serum metabolite profile differentiated between survivors and nonsurvivors, despite matching for patient characteristics. Thus, serum metabolites show potential as prognostic biomarkers for head and neck cancer patients. Lastly, we found that combining three metabolomics approaches resulted in the most comprehensive coverage of metabolite classes and the most complete description of the phenotype, for women with ovarian cancer. This Chapter also highlighted the need to address the influence of common risk factors on the serum metabolome. Taken together, the work presented in this thesis has provided further insight into the serum metabolite profile of metabolic disease and cancer in the context of diet and physical activity.
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    The Identification of Target Gene to Increase Immunotherapy Response in Patients with Solid Tumors using Experimental and Computational Approaches
    (2023-07) Nasr, Sahar; Wang, Edwin; Mahoney, Douglas; Bathe, Oliver; Bose, Pinaki
    Conventional cancer therapies have limitations which can lead to high recurrence rates and reduced quality of life. Immune checkpoint inhibitors (ICI) have been shown to have more durable responses and fewer side effects. This makes them an alternative treatment for solid tumors like bladder cancer and MSI-high colorectal carcinoma. However, many patients do not respond to ICI or develop resistance due to factors such as the absence of CD8+ T cells in the tumor microenvironment, dysfunctional CD8+ T cells, and impaired tumor-specific memory T cells generation. This study shows that inhibiting Sun1 enhances tumor-infiltrating lymphocyte infiltration, inhibits tumor growth in mice, and improves the response to anti-PD-1 treatment. Although the role of Sun1 in chromatin organization and gene expression regulation is not fully clear, its inhibition can upregulate the immune-related genes within the knockout cell lines. This approach suggests a potential strategy for enhancing ICI effectiveness in cancer treatment.