11 Notes - Hallmarks & Growth.pdf

Hallmarks of cancer  Self-sufficiency in growth signals  Insensitivity to growth-inhibitory signals  Altered cellular metabolism  Evasion of apoptosis  Limitless replicative potential (immortality)  Sustained angiogenesis  Invasion and metastasis  Evasion of...

Hallmarks of cancer  Self-sufficiency in growth signals  Insensitivity to growth-inhibitory signals  Altered cellular metabolism  Evasion of apoptosis  Limitless replicative potential (immortality)  Sustained angiogenesis  Invasion and metastasis  Evasion of immune surveillance  Genomic instability  Tumor promoting inflammation  [mn] an example of Darwinism = selection of the fittest to compete, survive, and reproduce.  Majority of the cells die, mostly by necrosis instead of apoptosis  The “fittest” survivors in the body / cells “society”  Don’t perform any specific function in the “society” (of the organism)  Do not contribute to the structure of the “society”  Profit from the “society”’ resources  Evade, escape, or fight against “society’s” controlling mechanisms  Eventually are the cause of early demise Self-sufficiency in growth signals  Growth signal – normally if there is a demand, I. Growth factor (GF) binds to its specific membrane receptor (GFR)  normally GFs are produced by surrounding & controlling cells as a response to damage or infections (PAMP or DAMP) II. Activated GFR → activates several signal proteins [transduction]  normally GFR activation is temporary and limited  has to be coordinated with other environmental signals: (ECM tension – integrins, focal adhesion) III. Transmission of the transduced signal across the cytosol (second messengers / cascade of signal transduction molecules) → to the nucleus  Parallel metabolic changes  Correlates with other signals including mechanical tension, PAMP and DAMP IV. Induction and activation of nuclear regulatory factors → initiate and regulate DNA transcription and the biosynthesis of other cellular components needed for cell division,  ribosomes, organelles & membrane components,  cell cycle regulatory proteins V. Entry and progression of the cell into the cell cycle → cell division  CC modifications: Dr M Hossu Notes 156  o I. Autocrine stimulation: produce their own growth factor: expression or dezinhibition of a GF gene (not mutated)  glioblastomas express both platelet-derived growth factor (PDGF) and the PDGF receptor  many sarcomas overexpress both transforming growth factor α (TGF-α) and its receptor (epidermal growth factor receptor - EGFR) o Stimulate stroma to increase production of GF (mostly through PAMP and DAMP signals) o II. Receptor “gain-of-function” → GFR altered, over-expressed, or escape parallel regulation  Mutation and gene amplifications in EpidermalGFR genes (ERBB1), mutated to stay active longer & overexpressed in 80% of squamous cell carcinomas of the lung, > 50% of glioblastomas, and 80% to 100% of epithelial tumors of the head and neck  increase co-activation from ECM ! focal adhesion kinase (FAK) is overexpressed or activated in multiple cancers and supports tumor cell proliferation, migration, and therapy resistance. Bergonzini & all: Targeting Integrins for Cancer Therapy - Disappointments and Opportunities. Front Cell Dev Biol. 2022 Mar 9;10:863850 o III. signaling path “gain-of-function” → convert proto-oncogenes to oncogenes  encoding mutated oncoproteins may promote cell growth, even in the absence of normal growth-promoting signals. o e.g. RAS (small G-protein) [30% of ALL studied cancers] or downstream proteins RAF, PI3K, AKT, stay active longer  mutation creating new oncogenes o e.g. BCR-ABL protein after ABL translocation in CML – excellent response to BCR-ABL kinase inhibitors like imatinib o IV & V nuclear transcription factors for cell cycle progression o normally cell cycle is controlled by cyclin-dependent kinases (CDKs) and their inhibitors (CDKI) o There are two main cell cycle checkpoints, (G1/S transition and G2/M transition), tightly regulated by a balance of growth-promoting and growth-suppressing factors, AND by sensors of DNA damage  transcription factor regulators also become oncoproteins (e.g. MYC amplification by 8:14 translocation)  Gain-of-function mutations: CDK4 or D cyclins (melanoma, sarcoma, glioblastoma)  Loss-of-function mutations or deletion: CDKIs (melanoma, pancreatic carcinomas, glioblastomas, esophageal cancers, certain leukemias, non–small cell lung carcinomas, soft-tissue sarcomas, and bladder cancers) Dr M Hossu Notes 157  Note:  normal genes than code for normal proteins / enzymes that are involved in cell proliferation are named proto-oncogenes. When mutated and induce uncontrolled proliferation will be named oncogenes.  Similar, genes that code inhibitory proteins are called tumor suppressor genes Insensitivity to growth-inhibitory signals o retinoblastoma gene (RB) [governor of cell cycle]  Was the first tumor suppressor gene to be discovered and is now considered the prototype of this family of cancer genes.  Biallelic loss of this gene is a common feature of several tumors, including breast cancer, small cell cancer of the lung, and bladder cancer and at increased risk for developing osteosarcomas and some soft-tissue sarcomas  The coded protein is a DNA-binding protein that integrates (through phosphorylation) progression vs cycle arrest signals.  Normaly it is kept “active” = hypophosphorylated, blocking S phase genes transcription  mutated = not very efficient in blocking progression o TP53 gene [guardian of genome] (17p13.1)  More than 70% of human cancers have a defect in this gene, and the remaining malignant neoplasms often have defects in genes upstream or downstream of TP53.  Biallelic abnormalities of the TP53 gene are found in virtually every type of cancer, including carcinomas of the lung, colon, and breast—the three leading causes of cancer deaths.  p53 protein is a short lived (20 min) transcription factor that triggers transcription of many anti-neoplastic genes based on DNA damage, hypoxia, telomere shortening  temporary cell cycle arrest and DNA repair:  if repair is successful it triggers upregulation of it’s own inhibitor and the cycle progress  permanent cell cycle arrest (senescence) with permanent chromatin changes  programmed cell death (apoptosis)  if mutated or inhibited can’t prevent the cell to stop proliferating if damage is not repair → damages are propagated to surviving daughter cells  proteins of several DNA viruses (e.g. E6 protein of high-risk human papilloma viruses) bind p53 and promote its degradation. o Loss of contact inhibition  Loss of cell-cell contact (in a wound or injury to the epithelium), disrupts the interaction between E-cadherin and β-catenin, Dr M Hossu Notes 158   → translocation of β-catenin to the nucleus, where it stimulates genes that promote proliferation; this is an appropriate response to injury that can help repair the wound.  Reestablishment of these E-cadherin contacts as the injury heals leads to β- catenin again being sequestered at the membrane and reduces the proliferative signal  Reduced cell surface expression of E-cadherin has been noted in many carcinomas, including those that arise in the esophagus, colon, breast, ovary, and prostate Evasion of apoptosis  Apoptosis = “Normal death” by two pathways that lead to apoptosis:  extrinsic pathway, o triggered by the death receptors FAS and FAS-ligand (on NK and CTL);  intrinsic pathway (mitochondrial pathway), o initiated by loss of growth factors, injury, ECM alterations, DNA damage, mitochondrial damage o → permeabilization of the mitochondrial outer membrane → release of mithocondrial molecules, (cytochrome c) o Controlled by tight balance of anti-apoptotic proteins of BCL2 family versus the pro-apoptotic proteins BAX and BAK.  Common final path → activation of cytosolic caspases  overexpression of the BCL2 type protein o 85% of B-cell lymphomas have a (14;18)(q32;q21) translocation. o 14q32, the site where immunoglobulin heavy chain (IgH) genes are found, o Juxtaposition of this transcriptionally active locus with BCL2 (located at 18q21) causes  most hematopoietic and solid tumors overexpress at least one member of the BCL2 family  chemotherapy and radiation therapy kill cancer cells mainly by inducing apoptosis via the intrinsic pathway. ← overexpression of BCL2 family members is believed to have an important role in the resistance of tumors to therapy Limitless replicative potential (immortality)  Normal labile/ stem cells reach “mitotic crisis” and die (through apoptosis) due to shortening of telomeres at the ends of chromosomes  telomere maintenance is seen in virtually all types of cancers,  85% to 95% of cases this is due to upregulation of telomerase that rebuild shortened telomeres  The remaining tumors use another mechanism to maintain their telomeres probably through DNA recombination: Reactivate telomerases to repair chromosomes after a breakage-fusion-bridge cycle (on a background of P53 deficiency)  Cancer stem Cells Dr M Hossu Notes 159   The continued growth and maintenance of normal tissues depends on a resident population of tissue stem cells that are capable of self-renewal. o in short-lived cells: bone marrow and epithelial cells (GI tract, skin, mucosas) o tissue stem cells and germ cells express telomerase  resistant to mitotic crisis o Stem cells may go into asymmetric division, only one daughter cell remains a stem cell; the non–stem cell daughter gains some differentiation  A least some cells in all cancers must be stem cell–like = cancer stem cells. o May arise through transformation of a normal stem cell or through acquired genetic lesions that impart a stem-like state on a more mature cell o are hard to identify molecularly o ongoing debate about their identity, their numbers in particular cancers, their source  It is hypothesized that like normal stem cells, cancer stem cells have a high intrinsic resistance to conventional therapies o low rate of cell division o the expression of protection factors like multiple drug resistance-1 (MDR1) / permeability glycoprotein (excretion pump) Genomic instability  high frequency of mutations within the genome of a cell line o DNA is usually most vulnerable during replication o “Fragile sites” may exist along exposed chromatin  inherited mutations of genes involved in DNA repair systems are at greatly increased risk for the development of cancer and certain neurodegenerative diseases  carcinomas of the colon changes in length of short repeats throughout the genome.  xeroderma pigmentosum have a defect in the nucleotide excision repair pathway after exposure to UV light,  BRCA1 and BRCA2, which are mutated in familial breast cancers, are involved in DNA repair. Altered cellular metabolism  All fast growing cells have high levels of glucose uptake and increased glycolytic pathway (conversion of glucose to lactose / fermentation / Warburg effect)  Provides metabolic intermediates that are needed for the synthesis of cellular components o Upregulates the activity of glucose transporters o Upregulates multiple glycolytic enzymes with the exception of last step (M2 isoform of pyruvate kinase) →it accumulates intermediary metabolites o Shunting of mitochondrial to lipid biosynthesis; o Upregulates usage of glutamine for amino-acids synthesis) Dr M Hossu Notes 160   Mechanism: o mostly through GF o inactivation of tumor suppressor genes. o Mutated enzymes that produce other metabolites (e.g. isocytrate dehydrogenase (IDH), succinate dehydrogenase (SDH), fumarate hydratase (FH))  Autophagy: in state of nutrient deficiency cells use their own organelles, proteins, and membranes as carbon sources for energy production to survive until nutrients are restored or programmed death intervene o Tumor cells are able to grow under marginal environmental conditions without triggering autophagy instead enter “dormancy” o it also make them resistant to therapies.  Mitochondrial metabolism is NOT blocked but switched from high ATP to metabolites and ROS o ROS is normally signaling for apoptosis. o If apoptosis is blocked ROS will change gene expression, and stimulate cancer cell proliferation, and at higher concentration will induce more mutations o Only high levels of ROS will induce damage; Fontana F, Anselmi M, Limonta P. Unraveling the Peculiar Features of Mitochondrial Metabolism and Dynamics in Prostate Cancer. Cancers. 2023; 15(4):119 Sustained angiogenesis  Like normal tissues, tumors require delivery of oxygen and nutrients and removal of waste products by the surrounding blood vessels; o presumably the 1- to 2-mm zone represents the maximal distance across which oxygen, nutrients, and waste can diffuse from blood vessels. o Early in their development, most tumors do not induce angiogenesis, are starved of nutrients, and remain small or in situ, possibly for years, until an angiogenic switch terminates this stage of vascular quiescence.  Growing cancers stimulate neoangiogenesis, o during which vessels sprout from previously existing capillaries, o however blood vessels are abnormal, and leaky  Endothelial cells also secrete growth factors and may contribute to tumor growth  Leaky blood vessels provide access of CC to a way of transport at distance = metastasis  It’s controlled by a balance between angiogenesis promoters and inhibitors;  Activators are factors produced by o the tumor cells themselves o inflammatory cells (e.g., macrophages) o other stromal cells associated with the tumors.  Proteases (from tumor cells or stromal cells in response to the tumor can release proangiogenic basic fibroblast growth factors (bFGF) stored in the ECM;  angiogenesis inhibitors (e.g. angiostatin, endostatin) are produced by proteolytic cleavage of plasminogen and collagen, respectively. o diminished Dr M Hossu Notes 161