Activation of Oncogenes (Proto-oncogenes to Oncogenes)

• Normal cells have genes called proto-oncogenes that help regulate normal cell growth and division. However, mutations or other alterations in these genes can transform them into oncogenes, which drive uncontrolled cell growth and proliferation.

• When an oncogene is activated, it can keep a cell constantly in a "go" state, overriding normal signals to stop or slow growth.

• Key Oncogenes Involved in Cancer:

  • RAS: Mutations in KRAS, HRAS, or NRAS genes (members of the RAS family) cause the RAS proteins to be permanently active, continuously sending growth-promoting signals to the cell.

  • MYC: Overexpression or mutations in the MYC gene can lead to abnormal activation of cell cycle progression and bypass normal checks on growth.

  • EGFR: Overexpression or mutations in the epidermal growth factor receptor (EGFR) gene can lead to excessive cell signaling that drives tumorigenesis.

    
    

Inactivation of Tumor Suppressor Genes

• Tumor suppressor genes normally function to regulate the cell cycle, repair damaged DNA, and promote apoptosis (programmed cell death) if a cell becomes damaged or abnormal. Mutations that inactivate these tumor suppressor genes prevent these checks and balances, allowing abnormal cells to continue dividing and survive.

• Key Tumor Suppressor Genes Involved in Cancer:

  • TP53 (p53): Often referred to as the “guardian of the genome,” p53 is responsible for inducing cell cycle arrest or apoptosis in response to DNA damage. Mutations in TP53 are found in over 50% of all cancers and allow cells to evade apoptosis despite having genetic damage.

  • RB1 (Retinoblastoma protein): The RB1 gene controls the cell cycle by preventing cells from entering the S-phase (where DNA replication occurs). Mutations in RB1 remove this control, leading to uncontrolled cell division.

  • PTEN: This gene acts as a negative regulator of the PI3K-AKT pathway, a key growth and survival pathway. Inactivation of PTEN leads to excessive signaling that promotes tumor growth.

Deregulation of the Cell Cycle

• Cancer cells often develop mutations in the key regulatory checkpoints of the cell cycle, allowing them to bypass normal control mechanisms and divide uncontrollably. These mutations typically affect genes that govern the progression through the different phases of the cell cycle.

• Key Cell Cycle Regulators Involved in Cancer:

  • Cyclins & Cyclin-Dependent Kinases (CDKs): Cyclins and their partner kinases are involved in regulating progression through the cell cycle. Overexpression of certain cyclins (e.g., Cyclin D) or mutations in CDKs can drive excessive cell division.

  • CDK Inhibitors (e.g., p21, p16): These proteins normally act as brakes on the cell cycle. Mutations or deletions in CDK inhibitors remove this brake, allowing uncontrolled progression through the cycle.

  
  

Avoidance of Apoptosis (Programmed Cell Death)

• Apoptosis is a vital process that ensures damaged or abnormal cells are eliminated. Cancer cells acquire mutations that help them resist apoptosis, allowing them to survive and proliferate even when they are damaged.

• Key Pathways and Genes in Avoiding Apoptosis:

  • BCL-2 Family Proteins: These proteins regulate apoptosis by controlling the mitochondrial pathway of cell death. Overexpression of BCL-2 (an anti-apoptotic protein) can block apoptosis and allow the cell to survive despite damage.

  • PI3K-AKT-mTOR Pathway: Mutations in this pathway can lead to resistance to apoptosis and promote cell survival. For instance, PIK3CA mutations lead to constant activation of the PI3K-AKT pathway, which suppresses apoptotic signals.

  
  

Sustained Angiogenesis (Blood Vessel Formation)

• For a tumor to grow beyond a certain size, it needs a blood supply to provide oxygen and nutrients. Normal cells require signaling to grow new blood vessels (angiogenesis) when needed. Cancer cells often gain the ability to promote angiogenesis excessively, enabling them to grow rapidly and metastasize (spread to other tissues).

Key Pathways in Angiogenesis:

• VEGF (Vascular Endothelial Growth Factor): Cancer cells often overexpress VEGF, a key molecule that promotes the growth of new blood vessels. This provides the growing tumor with the blood supply it needs to thrive.

Tissue Invasion and Metastasis

As cancer cells grow, they often acquire the ability to invade surrounding tissues and spread to distant organs. This process is known as metastasis and is responsible for the high morbidity and mortality associated with cancer.

Key Pathways Involved in Metastasis:

• Epithelial-Mesenchymal Transition (EMT): EMT is a process that allows epithelial cells (which are normally immobile) to become more mesenchymal-like (more migratory and invasive). During EMT, cancer cells lose adhesion molecules like E-cadherin, making it easier for them to invade surrounding tissues.

• MMPs (Matrix Metalloproteinases): These enzymes break down extracellular matrix proteins, enabling cancer cells to invade other tissues and spread.

Altered Metabolism (Warburg Effect)

Cancer cells often have altered metabolic pathways to support their rapid growth. This is often referred to as the Warburg Effect, where cancer cells rely more on glycolysis (the breakdown of glucose) rather than oxidative phosphorylation, even in the presence of oxygen. This helps cancer cells produce the energy and biomolecules needed for rapid proliferation.

Immune Evasion

Cancer cells often acquire mutations that allow them to evade detection and destruction by the immune system. This allows them to persist and grow in the body without being attacked by immune cells like T-cells.

Immune Evasion Mechanisms:

• PD-L1 (Programmed Death Ligand 1): Many cancer cells overexpress PD-L1, which binds to PD-1 on immune cells (especially T-cells) and inhibits the immune response. This helps the cancer cells avoid immune surveillance.

• Tumor Microenvironment: The microenvironment surrounding the tumor can suppress immune cell activity through various signals, further promoting immune evasion.