Hallmarks of Cancer PDF

# Hallmarks of Cancer All cancers show 8 fundamental physiological changes in their cells. These are called Hallmarks of cancer. SIAELSIE Therefore, Hallmarks of cancer by definition are the fundamental physiological changes that normal cells have to undergo to become cancerous. They include; 1. S...

# Hallmarks of Cancer All cancers show 8 fundamental physiological changes in their cells. These are called Hallmarks of cancer. SIAELSIE Therefore, Hallmarks of cancer by definition are the fundamental physiological changes that normal cells have to undergo to become cancerous. They include; 1. Self-sufficiency in growth signals. 2. Insensitivity to growth inhibitory signals. 3. Altered cellular metabolism. 4. Evasion of Apoptosis. 5. Limitless replicative potential (immortality). 6. Sustained Angiogenesis. 7. Invasion and metastasis. 8. Evasion of immune surveillance. These 8 hallmarks are enabled by 2 main factors: 1. Genetic instability 2. Tumor promoting inflammation. ## (1) Self-suppiciency in growth factors. Before going into detail, we need to talk about cell proliferation because this hallmark depends on it. Cell proliferation: the entire process of gene expression and cell division. It is activated by something called growth factors. * Growth factors bind to growth factor receptors to cascade cell division and gene expression. **Self-sufficiency in growth signals means cancer cells are able to create and respond to their own growth signals.** They do this via various mechanisms as follows: ### (i) Growth Factors. * **Normally, cells generate growth factors that can’t be used on their own receptors but rather on receptors of other/nearby cells.** This is the general "rule" and this rule helps to keep things in order. ### (ii) Cancer cells break this "rule" in 2 ways: 1. **They create growth factors that react on their own receptors.** For example, in glioblastoma, cancer cells release platelet-derived growth factor (PDGF) but it is exposed on PDGF receptors found on their own surfaces. 2. **They stimulate the stroma to secrete growth factors that would react on their parenchyma cells all the time.** ### (ii) Growth Factors Receptors. * **Growth factors have receptors** The activation of these receptors leads to the "initiatie" cascade of events that lead to cell proliferation, division, and growth. * **In cancer, there are changes in these receptors.** There are 2 common expression changes: 1. **Over-expression**: Cancer cells express **a lot of receptors** on its surface. **This can result in hypersensitivity of the receptor** and **not even overexposure caused by extra growth factors, all the receptors become activated.** This leads to the **over-production proteins** that gene expression. 2. **Changes in the strength of the receptors**: * **Mutations (such as in-frame point mutations) can occur** causing the receptors to always be active to cause cell growth. ## (iii) Downstream Signal-Transduction Proteins. * **In the process of cell proliferation, intracellular mechanisms are what cause the initiation of gene expression and cell division.** Both eventually lead to cell death. * **Mutations at some "rare" mechanisms could be an important hallmark of cancer.** ### First, let’s understand basic terminologies. **Proto-oncogenes:** These are normal genes in the body that encode for normal growth factors genes. **Their mutations lead to the formation oncogenes.** **Oncogenes:** Are genes derived from mutated proto-oncogenes and encode for oncoproteins like onco-growth factors. **Oncoproteins:** Are proteins formed from the expression (transcription & translation) of oncogenes. * **Normally signal transduction occurs via the activation of either RAS and ACL.** #### RAS * **RAS is a proto-oncogene that, if its active form (oncogene RAS) encodes for the expression of RAS protein, normal cell growth is achieved perfectly.** * **Any kind of mutation in the RAS proto-oncogene could lead to cell growth (hallmark).** **Normal pathway**: **RAS mutation pathway:** **ABL** * **Another important proto-oncogene is ABL, which is mostly responsible for the activation of RAS to initiate the RAS pathway.** * **It is only used when it is needed.** However, if cases of mutation, it could mutate and cause cancer. It occurs via the following steps: 1. **In the chromosomes, translocation of ABL and BCP genes (on the chromosomes) can occur.** 2. **This leads to the formation of ABL-BCP hybrid.** 3. **This hybrid has the properties of both ABL (cell growth) and BCP (make units/parts to each other).** 4. **The ASH domain of the hybrid is also called the tyrosine kinase domain.** 5. **The BCP domains/parts make phosphorylation easier** (on the proteins) 6. **This leads to the abnormal functioning of RAS → ↑ cell growth**. ## (iv) Nuclear Transcription Factors. * **Dysregulation of MYC protein promotes tumorigenesis by ↑ cell growth.** ## (v) Cell-cycle dependent kinases (CDK) problems. * **It is all cell potential responsible for checking if all is well at the cell cycle checkpoints of the G1/S and at the G2/M checkpoints.**