Cancer 1 + 2 PDF

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Thursday, 4 November 2021Cancer1. Growth signal autonomy to maintain proliferation: Normal cells require external stimulation from growth factors to promote entry into the cell cycle Cancer cells may have:- enhanced external stimulation eg: mutations in growth factor receptors or increaselevels of g...

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Thursday, 4 November 2021

Cancer

1. Growth signal autonomy to maintain proliferation: Normal cells require external stimulation from growth factors to promote entry into the cell cycle Cancer cells may have:

- enhanced external stimulation eg: mutations in growth factor receptors or increase levels of growth

- Lost this dependency due to: A. Activating mutations in signal transduction components B. Mutations in cell cycle components

2. Evasion of growth inhibitory signals: In order to maintain homeostasis, normal cells respond to inhibitory signals which regulate growth, differentiation and apoptosis. Cancer cells have lost this ability via:

- loss of activity of tumour suppressor genes such as p53, PTEN & Rb - Aberration in developmental signalling pathways

3. Evasion of apoptosis: In order to maintain fidelity, normal cells with DNA damage are removed via apoptosis Cancer cells evade apoptotic signals via:

- mutations that affect the intrinsic pathway of apoptosis - Mutations taht affect the extrinsic pathway eg. Aberrations in death receptor regulation

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4. Angiogenesis: Formation of new blood vessels In normal cells & tissue, angiogenesis only occurs under very specific physiological conditions e.g. active periods of growth, female reproductive organs and wound healing.

•Diffusion limit of oxygen through solid tissue is ~ 200 micrometres •Necrosis is caused by hypoxia or lack of oxygen (bright red areas are hypoxic: green indicates capillaries) •Tumours require vascularisation to grow into a large mass and to prevent of necrotic cell death •Rate limiting step in tumour growth •Facilitates metastasis •Angiogenesis is regulated by a balance between the levels of angiogenic inducers and angiogenic inhibitors •Many proangiogenic molecules are growth factors – key player is vascular endothelial growth factor (VEGF) •Normal angiogenic regulatory processes are disrupted so tumour vasculature is abnormal 5. Maintaining replicative immortality Normal cells shorten the ends of their chromosomes (telomeres) during every round of DNA replication which defines a finite number of cell doublings Telomeres: •Composed of repetitive DNA sequences (TTAGGG) and associated proteins •Protect ends of chromosomes and control chromosomal length •Shorten by 100-200 bp each DNA replication round due to limits of DNA polymerase needing an RNA primer

- telomerase is a form of reverse transcriptase that also contains the RNA template for the telomere repeat DNA

- maintains telomere length (telomeres can be seen in yellow fluorescence) Loss of telomeres normally limits the number of rounds of cell division

Cancer cells and stem cells

- produce telomerase - Maintain telomere length and immortality SUMMARY •Cancer can be classified into four major groups depending on the cell of origin and carcinomas derived from epithelial cells make up the majority of solid tumours. •There are several distinct cellular changes that distinguish a cancer cell from a normal cell. •Several changes directly impinge on growth regulation i.e. enhancement of pathways driving growth, together with a reduction in pathways inhibiting growth. •Growth and progression are further supported by enhanced survival and immortality •Tumours can promote the growth of their own blood supply.

Cancer 2 6. Invasion and Metastasis Normal cells maintain their location in the body and generally do not migrate Cancer cells have gained the ability to invade and spread (metastasise) to distant sites by: • Breaking cell-cell and cell - ECM attachment • Becoming more motile • Inducing angiogenesis to support ‘secondary’ tumour growth Primary tumour - site of origin

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Secondary tumour - metastases (traced back to primary tumour - same cell type) Metastatic cells show preferential spread to particular sites - ORGANOTROPISM Site of spread: • Close proximity to primary tumour

- direction of blood flow - Tumour cells get trapped in capillary bed • Distal/ non-obvious

- seed and soil hypotheses (paget) (Cells need to match with optimum environment)

- premetastatic niche (Lynden) (Distant site is prepared via circulating tumour derived factors)

Overview of the process of metastasis: Note: cells must also break cell-cell and cell-EMC contacts and change shape and become more motile

Src helps mediate breakdown of cell:cell contacts and cell:EMC contact • Invasive breast cancer cells with Hugh levels of Src activity in normal growth medium (time lapse over 24h) • Cells treated with small molecule Src kinase inhibitor (Time lapse over 24h) Invasion is facilitated by epithelial-mesenchymal-transition (EMT)

EMT - key regulators are transcription factors SNAIL and TWIST Loss of cell polarity and cell adhesion molecules e.g. E-cadherin ; changes in cell shape ; increase in mesenchymal markers e.g. N-cadherin : protease production

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Deregulating cellular energetics ( or reprogramming energy metabolic)

What is the rationale for cancer cells to utilise aerobic glycolysis • Cancer cells are frequently hypoxic - lack oxygen for oxidative phosphorylation • Process of glycolysis also generates intermediates for biosynthetic pathways such as growth Excessive glucose metabolism via the Warburg effect can be explored therapeutically and additionally used as a diagnostic tool. Avoiding immune destruction • The immune system can recognise and eliminate cancer cells - immune surveillance • T cells are key immune cells in cell killing - cytotoxic T cells - includes CD4, CD8, Natural killer cells

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Cancer immunity cycle

Cytotoxic T cells can kill target cells by triggering apoptosis via: •Injecting granzymes into the target cell – directly cleave and activate effector caspases •Initiating the extrinsic route of apoptosis by activating death receptors Avoiding immune destruction: • Cancer cells can evade the immune system by: - loss of tumour antigens - Down regulation of antigen-presenting molecules (APCs) - Over-expression of immune checkpoint proteins and anti-apoptotic proteins Inflammation and Cancer •Tumour cells secrete cytokines that attract tumour-associated macrophages (TAMs) •TAMs produce growth factors, cytokines and reactive oxygen/nitrogen species (cause DNA mutation *) •Cytokines activate transcription factors that can drive cell proliferation and angiogenesis

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Stem cells and cancer stem cells (CSCs) Stem cell: ability to self renew and simultaneously form differentiated progeny •Embryonic stem cell – from inner mass of early embryo that can differentiate into different cell types during development •Adult stem cell- in regenerative tissue, replaces cells that mature and die

CSCs: •Are subpopulations within a tumour that are thought to initiate and maintain the cancer •May be responsible for: - Heterogeneity of tumours - Tumour plasticity - Migratory abilities •Can be identified (and isolated) through various and/or tissue specific stem cell markers e.g. CD44 (breast and pancreas), CD133 (colon, prostate, brain) •More likely to survive anti-cancer treatments •May arise from deregulation of self-renewal pathways e.g. Wnt and Hedgehog SUMMARY •There are six established hallmarks of cancer – unregulated proliferation, evasion of growth inhibitory signals, evasion of apoptotic cell death, unlimited replicative potential, blood vessels formation within the tumour and invasion and metastasis. •Emerging hallmarks i.e. alterations in energy metabolism and avoiding immune destruction also contribute to cancer formation •Other characteristics including inflammation can also enable tumour formation •It is now thought that the tumour population is comprised of tumour cells and cancer stem cells (CSCs) •CSCs maintain the tumour population and are resistant to anti-cancer treatments

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