Neoangiogenic effects of thermally processed frying oil consumption in animal and cell-based models of triple negative breast cancer

Oyirifi, Ashley B.

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https://hdl.handle.net/2142/127155 Copy

Description

Title

Neoangiogenic effects of thermally processed frying oil consumption in animal and cell-based models of triple negative breast cancer

Author(s)

Oyirifi, Ashley B.

Issue Date

2024-11-22

Director of Research (if dissertation) or Advisor (if thesis)

Helferich, William

Doctoral Committee Chair(s)

Nelson, Erik

Committee Member(s)

• Madak-Erdogan, Zeynep
• Engeseth, Nicki

Department of Study

Food Science & Human Nutrition

Discipline

Food Science & Human Nutrition

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

breast cancer, metastasis, diet

Abstract

Background: Breast cancer survivorship is a critical period in which women who have undergone successful treatment of primary breast cancer seek to minimize risks of metastatic recurrence. Lifestyle modification, particularly diet modification, is a tactic to reduce the risk of recurrence risk during the survivorship period. In the US, fried food comprises a large proportion of the diet. There is a need understand how frying oil, which can make up as much as 20% of the weight of fried food, may impact breast cancer metastasis. Specifically, it remains unclear what pro-metastatic processes are promoted by TPO consumption and what molecular mechanisms or pathways may causally link TPO to metastatic progression. Aims: The study was guided by the following aims: (1) To consolidate the literature findings from the last 10 years on TPO and health outcomes and gain insights related to cancer, (2) To assess the role of TPO-induced angiogenesis in metastasis in vitro and in vivo, and (3) To explore how TPO may impact canonical regulators of angiogenesis and oxidative stress. Results and Insights: From the consolidation of TPO literature, three major insights were obtained: 1) System-wide oxidation and inflammation are widely reported responses to TPO consumption 2) There is wide methodological variation in assessments of TPO-driven health outcomes, which may impact the quality of insights 3) Cancer, brain health, and reproductive health are areas with the largest paucity of published TPO-related information. When seeking to understand the drivers of TPO-induced breast cancer metastasis, we learned that angiogenesis is likely a primary driver for high metastatic loads in animals consuming TPO compared to fresh oil. Four primary observations supported this finding: (1) No indication of a TPO-induced proliferative response or epithelial to mesenchymal transition was observed in in vitro or in metastatic tissue from TPO- or fresh oil-fed mice. (2) Gene expression analysis of metastatic lung tissue revealed that two markers of angiogenesis, VEGFA and CD31, were upregulated in TPO-fed animals grafted with 4T1 cells compared to fresh oil-fed animals. The gene expression data were supported by increased circulating concentrations of the VEGFA protein in TPO-fed mice. (3) In breast cancer cell lines, TPO exposure elicited pro-angiogenic phenotypes as demonstrated by up to a 1.8-fold increase in VEGF secretion from breast cancer cell lines exposed to the polar fraction of TPO and the formation of HUVEC microvessel networks that were two times longer for HUVECs, when exposed to the secretome from 4T1 cells exposed to TPO than for those formed in the presence of the secretome from untreated 4T1 cells. (4) In a model of late-stage TNBC, the increased metastatic burden driven by TPO consumption was ameliorated via an angiogenesis blockade (anti-angiogenic multikinase inhibitor that targets angiogenic signaling receptors). Finally, in seeking to develop hypotheses that can guide future research around TPO-driven angiogenesis, tests for TPO-associated peroxidation, signaling factors, ROS accumulation revealed three main insights: (1) In serum of non-tumor bearing mice consuming either fresh oil or TPO 1.7-fold higher concentrations of malondialdehyde, a secondary marker of lipid peroxidation, was found in TPO-fed animals’ serum. (2) Three proangiogenic cytokines are excreted from 4T1 cells in higher concentrations when exposed to TPO. (3) When exposed to increasing concentrations of TPO-PF, a dose dependent correlation between TPO exposure and intracellular ROS accumulation was observed. When fit to an exponential curve, the correlation was considered moderate to strong. The ROS effect was ameliorated with a free radical scavenger, TBHQ. These data can lay the foundations for future research around the causal mechanisms that drive TPO-modulated angiogenesis. Conclusions: The bibliographic research in the present dissertation reveals that TPO has been reported throughout 10 years of literature to enact molecular and tissue level changes in circulation and tissues. However, there is a gap in the literature on information about breast cancer metastasis. The experimental research reported here demonstrates that TPO impacts metastasis in an angiogenesis mediated manner. TPO was shown to impact intermediaries of angiogenesis (circulating lipid peroxidation, pro-angiogenic cytokine secretion, ROS accumulation) offering a glimpse into possible mechanism by which TPO modulates angiogenesis to affect metastasis. The authors conclude that angiogenesis is likely a primary driver for TPO-associated metastasis and offer pathways to explore to understand causal relationships between TPO and angiogenesis. More preclinical work is needed to uncover causals relationships and clinical samples or investigations are necessary to find translational and actionable uses of the findings presented in this dissertation.

Graduation Semester

2024-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/127155

Copyright and License Information

Copyright 2024 Ashley Oyirifi

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