Hallmarks of Cancer

• The Hallmarks of Cancer, detailed in a 2000 paper by Douglas Hanahan and Robert A. Weinberg, identifies key characteristics of cancer cells.

Genetic Basis of Cancer

• Oncogenes, derived from normal host genes (proto-oncogenes), result from gain of function mutations.
• Tumor suppressor genes undergo loss of function mutations.
• Transformation involves multiple genetic alterations that drive normal cells into malignant ones.

Characteristics of Transformed Cells

• Transformed cells form foci instead of monolayers in tissue culture.
• These cells exhibit anchorage-independent growth.
• They form tumors when injected into immunologically compromised animals.

Complexity and Essential Alterations

• Over 100 distinct types of cancer and tumor subtypes exist within specific organs.
• Hanahan and Weinberg proposed six essential alterations in cell physiology that dictate malignant growth.

Hallmarks of Cancer

• Sustaining proliferative signaling
• Evading growth suppressors
• Resisting cell death
• Enabling replicative immortality
• Inducing angiogenesis
• Activating invasion & metastasis
• Deregulating cellular energetics
• Avoiding immune destruction

Cancer Cell Behavior

• Cancer cells ignore 'Stop' signals.
• They produce their own 'Go' signals.
• Cancer cells resist cell death.
• They ensure they have a nutrient supply by stimulating the growth of new blood vessels.
• The cells also migrate and spread to different sites.

Sustaining Proliferative Signaling

• Normal cells need mitogenic growth signals (GS) to transition from a quiescent to an active proliferative state.
• These signals are transmitted via the Ras/Raf/MEK/ERK pathway.
• Many oncogenes mimic normal growth signaling.
• Epigenetic deregulation can provide chronic growth-promoting signals.
• It's the first of the six acquired capabilities to be defined.
• Alterations in downstream cytoplasmic circuitry processing GF receptor signals result in acquired GS autonomy.
• Example: SOS-Ras-Raf-MAPK cascade.
• Around 25% of human tumors have altered Ras proteins, releasing mitogenic signals without normal upstream stimulation.
• Half of colon cancers have a mutant Ras oncogene; the other half have mutations with the same phenotype.
• GF receptors carrying tyrosine kinase activities are often overexpressed in cancers.
• Increased receptor numbers can make cells hyperresponsive to GF levels that wouldn't normally trigger proliferation.
• The epidermal GF receptor (EGF-R/erbB) is upregulated in stomach, brain, and breast tumors, overexpressed in stomach and mammary carcinomas
• Ligand-independent signaling: Truncated EGFR versions lacking cytoplasmic domains fire constitutively.
• Cancer cells switch extracellular matrix receptors (integrins), favoring progrowth signal transmission.
• Ligand-activated GF receptors and progrowth integrins activate the SOS-Ras-Raf-MAP kinase pathway.
• Three molecular strategies for achieving autonomy: altering growth signals, transmembrane transducers, or intracellular circuits.
• Heterotypic signaling involves growth factors stimulating proliferation between different cell types.
• Cancer cells synthesize GFs, creating autocrine stimulation feedback loops.
• Glioblastomas produce PDGF, and sarcomas produce TGFα.

Evading Growth Suppressors

• Antiproliferative signals maintain tissue homeostasis through extracellular matrix and intracellular inhibitors.
• Antigrowth signals force cells into a quiescent G0 phase or a terminally differentiated postmitotic state.
• pRb (retinoblastoma protein) is a direct regulator of the cell cycle acting as an important tumor suppressor.
• pRb activity is regulated by extracellular signals to permit temporary proliferation and ensure normal tissue homeostasis.
• TGFbeta suppresses expression of cMyc gene, and increases synthesis of the p15 and p21 CDKis factors which inhibit cyclin activities and Rb phosphorylation.
• Cells can become unresponsive to TGFbeta through receptor downregulation, mutant receptors, Smad4 mutation or viral proteins sequestering Rb.

Role of p53

• Intracellular monitoring system is key for the p53 protein.
• p53 senses unrepaired DNA damage and other physiologic imbalances.
• The p53 pathway induces programmed cell death in severe cases.

Resisting Apoptosis

• Growth is determined by proliferation rates versus cell attrition (cell death).
• Three distinct mechanisms of programmed cell death need to be circumvented by cancer cells.
  • Apoptosis
  • Necrosis
  • Autophagy
• Apoptosis, or programmed cell death, involves collapse, protein degradation, and DNA fragmentation, then corpses are engulfed by neighboring cells, first defined in 1972.
• Types of Cell Death: Necrosis involves premature cell death from injury or infection and is uncontrolled, while Apoptosis avoids eliciting inflammation and is controlled.

Necrosis vs. Apoptosis

• Necrosis involves cellular swelling, broken membranes, no need of ATP and an uncontrolled cell death resulting in inflammation
• Apoptosis involves cellular condensation, intact membranes, requires ATP, and a controlled and phagocytosed cell death without tissue reaction or inflammation
• Internal apoptosis stimuli include genetic damage, lack of oxygen, high calcium concentration, and oxidative stress.
• External stimuli include:
  • Tumor Necrosis Factor alpha (TNFα)
  • Lymphotoxin (TNFß)
  • Fas ligand (FasL)

Apoptosis Players: Caspases

• These include cysteine-dependent aspartate specific proteases.
• Caspases have cysteine at active site and cleave targets after aspartic acid residues.
• They exist in the cytosol as proenzymes and when activated by other caspases result in proteolytic cascade.
• Two Caspase Types
  • Initiators: which are need to dimerize to become active and undergo self cleavage
  • Executioners: which are proteolytically cleaved by Initiator Caspases to become activate
• Main Pathways
  • Intrinsic: Mitochondria Mediated by releasing contents into the cytoplasm
  • Extrinsic: Signaling through Death Ligand

Intrinsic Pathway

• Outer Mitochondrial Membrane Permeabilization (MOMP), releasing Cytochrome C, causing Apoptosome Formation, and activating effector Caspases

Extrinsic Pathway

• Signaling through Death Receptors by signaling through Death Ligand resulting in Effector Activation

• Death receptors include TNFR family, Fas (CD95) and Death Ligands include TNFalpha, CD95L (FasL) causing downstream signaling

• Key Targets of Proteolysis:

  • Protein kinases (e.g., FAK)
  • Nuclear Lamins
  • Cytoskeletal proteins
  • Caspase activated DNAse (CAD)

Corpse Clearing

• A defining feature of apoptosis is the quick clearance of dying cells
• Macrophages release anti inflammatory when ingesting apoptotic cells and proinflamatory mediators.
• Changes in surface of plasma membrane with the exposure of phosphatidyl serine (PS) signal phagocytes to consume cell
• Survival signals (IGF1/IGF1R), Death (FasL/FasR, TNFα/TNFR1), sensors monitor cellular well being triggering signaling pathways
• Effector proteins like Caspases and Initiator Caspases will be triggered when irregularities are detected.
• Apoptosis suppression: Transgenic has tumors in mice when P53 suppressor is activated