Characterization of Key Signaling Pathways in Homeostasis and Cancer

Xi, He (2024). Characterization of Key Signaling Pathways in Homeostasis and Cancer. PhD thesis The Open University.



1.1 General introduction
1.1.1 Stem cell signaling in tissue health and cancer genesis Stem cells play a pivotal role in maintaining tissue homeostasis and have garnered significant attention for their involvement in cancer initiation and progression. Here, I summarize key concepts to be addressed in the thesis aimed at unraveling the intricate signaling mechanisms that regulate both normal stem cells and cancer stem cells (CSCs) and shedding light on their impact on tissue health and cancer genesis.
Stem cells, which are characterized by their ability to self-renew and their capacity to give rise to various cell lineages and differentiated to mature cell type, are crucial for tissue maintenance. They reside within specialized microenvironments, called niches, that provide essential regulatory cues (Figure 1, upper panel).In reference to the niche, stem cells undergo asymmetric or symmetric division. Asymmetric division generates two daughter cells: one remains a stem cell if remains within the niche, while the other gives rise to progenitor cells undergo non-self-renewal proliferation and subsequent differentiation. Symmetric division can produce either two daughter stem cells or two progenitor cells. These cells contribute to tissue regeneration, ensuring the continuity of normal physiological processes. However, dysregulation of stem cell development, such as in the case of unregulated proliferation, can lead to the formation of tumors (Figure 1, lower panel).
Understanding these processes has been a central focus of normal stem cell regulation and CSC dysregulation. Tumors can arise from uncontrolled proliferation of stem cells or progenitor cells with acquired self-renewal ability. The concept of CSCs has revolutionized therapeutic strategies by recognizing the pivotal role these cells play in tumor development.
My thesis aims to decipher some of the signaling pathways governing both normal and cancer stem cells, emphasizing the importance of maintaining a delicate balance between pro- and anti-proliferative signals. Perturbation of this balance can result in uncontrolled cell growth and impaired differentiation, ultimately leading to tumorigenesis.
To investigate the mechanism that governs stem cell proliferation and differentiation, I studied the behavior of cells in the intestinal and skin epithelium, as well as hematopoietic cells within the bone marrow. These tissues are characterized by high rates of turnover and significant regeneration capacity. In addition, these tissues and organs have been previously studied with known stem cell markers or methods to identify stem cells, thus making them ideal models for understanding stem cell regulation. Perturbation of the development of the bone marrow or intestine can lead to diseases such as leukemia and colorectal cancer respectively, making them valuable for studying the behavior of stem cells during cancer genesis.

1.1.2 Aims
Rationale: Stem cells reside in a niche, where intricate signaling maintains them in an undifferentiated state and ensures a balance between inhibition and promotion of proliferation. This leads to my general hypothesis: Perturbation of the control of proliferation, or the balance between proliferation and differentiation leads to overproduction of stem cells, resulting in the initial step of tumorigenesis. My thesis focused on testing this hypothesis via investigation of the following specific signaling pathways in Stem Cell regulation: I investigated how disruptions in Wnt and BMP pathways impact stem cell behavior, potentially shifting their development toward increased proliferation at the expense of reduced differentiation.
I. The PTEN-Akt pathway in converging BMP and Wnt signalling: I examined the central role of the PTEN-Akt signalling pathway in mediating the interplay between Wnt and BMP signalling, with disruptions exacerbating Tumour-initiating stem cell (TSC) proliferation.
II. The Cox2-PGE2-EP4 Pathway in TSC microenvironment: I explored alterations in the Cox2-PGE2-EP4 pathway within the tumour microenvironment and how it fosters a niche that is conduct conducive to TSC survival and growth.
III. Cross talk between TSCs and Tumour Microenvironment (TME): I studied how the alterations in TME-associated BMP, PTEN-Akt, and Cox2-PGE2-EP4 signals promote TSC proliferation and self-renewal.

Objectives: By dissecting how these signalling pathways affect normal and cancer stem cells, my thesis seeks to deepen our understanding of stem cell regulation in healthy tissues and the dysregulation in cancer, thereby providing valuable insights into tumorigenesis. while also identifying potential therapeutic targets.

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