9/29 Flashcards
6 Hallmarks of Cancer
Sustaining cell proliferation
Evading growth suppressors
Activating invasion and metastasis
Enabling replicative immortality
Inducing angiogenesis
Resisting cell death
2 Emerging Hallmarks and 2 Enabling Characteristics of Cancer
Emerging Hallmark:
Avoiding immune destruction
Reprogramming of energy metabolism
Enabling Characteristics:
Genome instability and mutation
Tumor-promoting Inflammation
Sustaining Proliferative Signaling
Make GFs and receptors like RTKs and can respond to the stimulus in an autocrine manner
Stimulate adjacent normal cells to stimulate proliferation
Overexpress GFs, making cancer cell hyperresponsive to growth stimulus, alter GF receptors by mutation to make constitutionally active
Somatic mutations can lead to upregulation of downstream signaling, lessen need for GF ligand
Disable senescence signaling
Evading Growth Suppressors
Protein Regulators of Cell Cycle-
1. RB: transduces growth inhibitory signals from outside the cell, loss of this leads to increased cell proliferation
- TP53: if genome is excessively damaged or resources are too low cell proliferation is halted, can cause apoptosis if too much damage
If lost then can proliferate with damage, creates genome instability
Contact Inhibition- cells normally stop proliferating once touch each other
1. Merlin: encoded by NF2, mutated in neurofibromatosis 2
- LKB1: associated with Peutz-Jegher syndrome
Resisting Cell Death: Apoptosis
Loss of TP53 function, increased expression of anti-apoptotic molecules like Bcl2, downregulate pro-apoptotic molecules like Bax/Bam, short circuit death effector molecules so they can’t execute their function
Intrinsic pathway is more relevant to cancer than extrinsic pathway
Resisting Cell Death: Autophagy
Autophagy enables cells to breakdown organelles to recycle the catabolites, occurs during periods of low nutrition
Increase autophagy during nutrient starvation, radiotherapy, and chemotherapy to help cope with Intervention
Can promote/prevent cancer depending on the situation
Inhibit apoptosis/autophagy: PI-3 kinase, AKT, and mTOR are stimulated by Growth signals
Beclin-1: induce autophagy and member of family that binds Bcl2, LOF increases cancer susceptibility, suggests induction of autophagy may be barrier to tumor development
Resisting Cell Death: Necrosis
Necrotic cells die and release their contents into the local tumor microenvironment
Releases proinflammatory factors that recruit inflammatory cells to tumor, can be tumor promoting by fostering angiogenesis, tumor cell proliferation, and invasion
Tumors may have an advantage if they can tolerate some degree of necrosis
Enabling Replicative Immortality
Normal cells are only capable of limited cell division cycles, telomeres shorten with each replication
Telomerase lengthens the telomeres for cancer cells
Inducing Angiogenesis
VEGF is potent inducer of angiogenesis, upregulated by hypoxia and oncogene signaling
Angiogenesis inhibitors: endogenously formed from proteolytic cleavage of structural proteins
Thrombospondin (TSP-1), plasmin (angiostatin), type 18 collagen (endostatin)
Bone marrow cells contribute to tumor angiogenesis like macrophages, PMN, mast cells, myeloid progenitors
Bone marrow-derived vascular progenitor cells migrate into tumors and become incorporated into neovasculature as pericytes/endothelial cells
Activating Invasion and Metastasis
Steps for invasion:
- Local invasion
- Intravasation by tumor into adjacent blood/lymphatic vessels
- Extravasation of transient cancer cells from vessel to distant tissue
- Metastatic tumor formation from microscopic to macroscopic lesions
Gene expression changes to reduce cell-cell affinity (decrease expression of cadherins) and enhance cell motility/infiltration
Invasion/metastasis regulated by epithelial-mesenchymal transition, colored by tumor cells
Use EMT to invade, resist apoptosis, and disseminate
EMT leads to spindle shaped cell and loss of cell-cell cohesion, increased motility and expression of ECM degrading enzymes
Stromal cells help with invasive behavior
Enabler: Tumor Promoting Inflammation
Provides bioactive molecules to tumor microenvironment like GFs, pro-angiogenic factors, factors that alter ECM to promote invasion/metastasis, and can induce EMT
Generates ROS that can damage DNA, leading to mutation and genetic instability
Emerging Hallmark: Reprogramming Energy Metabolism
Warburg Effect: cancer cells limit energy production to glycolysis (state called aerobic glycolysis), has activated oncogenes (MYC, RAS) and mutated tumor suppressors (TP53)
Cancer cells grow in relatively hypoxia environment, diverts respiratory intermediates into other biosynthetic pathways like AA/nucleoside synthesis
Upregulate GLUT1
Non-uniform tumor cell population: some are glucose dependent and secrete lactate, others use lactate from neighbors are energy source fornztCA cycle
Emerging Hallmark: Evading Immune Destruction
Innate and adaptive Immunity contribute to preventing tumor formation and progression
Immunomodulary therapies may make cancer cells more susceptible to immune-mediated destruction and be effective against cancer
Tumor Microenvironment
Cancer stem cells: origin is unclear, capable of self-renewal, can form new tumors, express same markers as normal stem cells
Endothelial cells: facilitate angiogenesis
Inflammatory cells: can promote tumor progression
Fibroblasts: associated with tumor, can promote cancer cell proliferation, angiogenesis, invasion/metastasis
Targeting the Cancer Hallmarks
Sustaining Proliferative Signaling: EGFR inhibitors
Evading Growth Suppressors: cyclin-dependent kinase inhibitors
Avoiding Immune destruction: immune activating anti-CTLA4 mAb
Enabling replicative Immortality: telomerase inhibitors
Tumor-promoting Inflammation: selective anti-inflammatory drugs
Activating invasion/metastasis: inhibitors of HGF/c-Met
Inducing Angiogensis: inhibitors of VEGF signaling
Genome Instability and Mutation: PARP inhibitors
Resisting Cell Death: proapoptotic BH3 mimetic
Deregulating Cell Energetics:
