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hallmarks of cancer

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sustaining proliferative signaling evading growth suppressors activating invasion and metastasis enabling replicative immortality inducing angiogenesis resisting cell death inflammation escaping the immune system

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sustaining proliferative signlaing

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normal tissues control release of growth factors that move cells into cell cycle cancer cells have learned to deregulate growth factor signal control cell surface receptors that eventually activated intracellular tyrosine kinases autoproduction of growth factor by cancer cells cancer cells may stimulate stromal cells to produce growth factors increase cancer cell growth factor receptor number growth factor structual alterations activation of downstream components like philadelphia chromosome

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somatic mutations activated

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B-RAF mutation leads to activation mitogen activated pathway (MAP kinase) in 40% melanomas, Pi3K mutation in colon cancer

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loss of negative feedback

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ras gene hurts GTPase activity needed fro negative feedback of proliferation PTEN phosphatase mutation will amplify Pi3K signaling leading to tumorogenesis mTOR kinase abnormalities amplifies Pi3K activity all of the above increase push sustained proliferation

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evading growth suppressors

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dozens of tumor suppressor genes known, regulate decisions for proliferation or activate senescence/apoptotic programs

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Rb gene

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loss of gatekeeper cell cycle signals that allow for cell proliferation, mainly outside cell

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TP53

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intracellular regulator of stress that leads to cell slow down, or if severe, apoptosis in the unmutated state

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loss of contact inhibition

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NF2 gene, neurofibromatosis, loss of cell adhesion instructions when gene mutates, thus tumor suppressor LKB1 suppression mutation will allow myc induced transformation

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TGF beta

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anti prolifeative suppressor effects, if mutated and inactivated cancer can start

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hayflick hypothesis

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cultured cells show contact inhibition, do not pile on top of one another, abolished in cancer in vitro

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driver mutations

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provide a small selective growth advantage to a cell, but over years can produce a mass of a billion cells

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passenger mutations

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found in cell replenishing tissue (GI and GU epithelium) are preneoplastic, many are noncoding mutations or epigenetic mutations ped tumors have less passenger mutations and are less invasive

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mut-Driver genes

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20K protein coding genes 125 are mut-driver genes, 54 oncogenes and 71 TSGs, require 5-8 hits for malignancy translocations (ALK), amplifications (myc family), and deletions add anotehr 15-20 real driver genes for a total of 138 hereditary tumors not mut-Driver genes

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resisting cell death-apoptosis

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extracelular death signals are fas ligand/receptor intracellular death inducing signals come together to activate normally latent proteases (caspases), proteolysis with progressive disassemblage and then consumed apoptosis counterbalanced by anti apoptotic mechanisms including bcl genes loss of TP53 suppressor gene circumvents apoptosis

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necrosis

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proinflammatory and tumor promoting potential necrotic cells become bloated and explode leading to inflammatory infiltrate in contrast to autophagy where cells withe and die inflammatory cells foster angiogenesis, cancer cell proliferation, invasiveness effect engenders tumor growth rather than apoptosis

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enabling replicative immortality

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normal cells can only divide so many times before they become senescent until crisis most cells in crisis die, but a few circumvent this and become immortal hayflicks hypothesis again, rare cells overcome senescence and go on to immortalizations telomers protecting the ends of chromosomes are involved in unlimited proliferation end of cell division depend on telmere during division which shorted with each cell cycle telomere loss, senescence or crisis/apoptosis, but some cells escape due to continued (upregulated) telomerase activity, causing cancer its possible loss of p53 and telomerase keeping longer telomeres enhance tumorigenesis

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telomerase

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activating the WnT pathway enhancing cell proliferation DNA repair and RNA polymerase function tumor promoting for breast cancer is the loss of telomerase moving to a malignant phenotype then regaining telomerase to stabilize the malignant genome

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angiogenesis

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tumors need delivery of nutrients and O2 with removal of waste metabolites and CO2 important for normal embryological development, but stops after birth except for wound healing and menses counter balance controls VEGF is positive vascular endothelial growth factor transpondins are negative

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VEGF

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gene encodes ligands that stimulate blood vessel growth, upregulated by hypoxia or oncogene signaling ligands can hide in the extracellular matrix waiting to be activated by proteases FGF can sustain angiogenic effects of VEGF TSP-1 counteracts angiogenesis by binding endothelial receptors and counteracts proangiogenic stimuli

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tumor angiogensis

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precocious capillary sprouting convoluted and excessive vessel branching distorted and enlarged vessels, erratic blood flow microhemorrhaging leakiness and abnormal levels of endothelial proliferation and apoptosis tumor AG induced early in tumor growth, strongly associated with malignant microinvasion

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gradations of AG switch

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oncogenes Ras or Myc which are also giving proliferative signals immune inflammatory cells induce angiogenesis

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AG counterbalance factors

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TSP-1, plasmin fragments, endostatin proteins, dozens of other proteins, agents probably normally serve as a physiological regulators that modulate transitory AG during wound healing or tissue remodeling may help stop neoplasias that are trying to start

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activating invasion and metastasis

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change in cell shape and adherance to other cells and extracellular matrix e-cadherin loss, a key cell to cell adhesion molecule, allows for invasion and metastasis n-cadherin, a cell-cell/matrix attachment protein whose upregulation is associated with embryogenesis and inflammation inflammation and metastasis are multistep processes called the invasion-met cascade

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Invasion-Met cascade

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local invasion intravasation of cancer cells into nearby blood and lymph vessels transit of cancer cells through blood or lymphatics escape of cancer cells through lumina to distant parenchyma forming micromets finally growth to macrometastasis called colonization

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Epithelial Mesenchyme Transition

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epithelial cells can acquire the ability to invade, resist apoptosis, and to disseminate Co-opt embryonic morphogenesis and wound healing will lead to invasion and mets transcription factors (snail, slug, twist, Zeb) do so in embryogenesis, andnow as we know, in carcinogenesis by affecting loss of adherance junctions and cell shape changes expression of matrix degrading enzymes, increased motility, and increased resistance to apotosis many of these factors directly repress E-cadherin

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stromal cell invasion and metastasis

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secretion of CCl5/RANTES from mesenchymal stem cells stimulates invasive behavior of cancer cells macrophages at the periphery of a tumor secrete metalloproteaases and cathespins which degrade normal matrix making invasion possible tumor associated macrophages (TAMs) supply epidermal growth factor to breast cancer cells, with reciprocal stimulation of the macrophages by CSF from the tumor cells

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colonization

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many micromets remain as micromets and never develop into visible macromets supressor tumors may stay such for decades (breast and melanoma) have figured out how to colonize tissue specific colonization (lung likes brain and adrenals) must be special programs that facilitate possible reseeding back to the primary tumor signaling a permissive tumor microenvironment

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genome instability

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loss of tumor suppressor genes, the guardians of the genome, best example is TP53 caretaker defects include detecting DNA damage and activating repair machinery direct repair of DNA inactivating and intercepting mutagenic molecules before the damage DNA loss of telomeric DNA generates karyotipic instability with amplification and deletion of chromosomal segments, thus telomerase is a big enabler or endless replication

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comparitive genomic hybridization

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CGH shows gains and losses of gene copy at certain sites of the genome, analyzed by microarray part of genomic instability next generation sequencing revealing defects in the cancer exome with potential therapies

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tumor promoting inflammation

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tumor destructive inflammatory cells seen in tumors supply bioactive moleculares to the tumor microenvironment (growth factors to sustain proliferative signaling, survival factors that limit cell death, proangiogenic factors, extracellular matrix modifying enzymes that help AG, invasion, metastasis can secrete reactive oxygen specifes that are mutagenic leading to further genomic instability and thus heightened malignancy

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reprogramming energy metabolism

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warburg effect, a shift from oxidative phosphorylation to glycolysis 18 fold decrease in ATP cancer cells upregulate GLUT 1 transporter to help counteract loss of oxidative phosphorylation, basis of PET scans associated with activated RAS and MYC and mutant tumor suppressor shift in production to other building blocks needed for active proliferation

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evading immune destruction

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immune surveillance has long been thought to ID and destroy nascent tumors, melanoma strongly infiltrated with lymphocytes at the base tumors we do see have somehow tricked the immune system to avoid detection immunosuppressed patients have higher incidence of cancer both innervate and adaptive immunity play a role donor derived tumors that arise in recipients now a role in therapy, ex) dendreon

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tumor microenvironment

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complex intermingling of supporting stroma matrix and mesenchymal cells cancer stem cells resistant to chemo and radiation explains the disease recurrence after therapy cells may morph into mesenchymal supporting stromal cells genetic heterogeneity as cancers proceed NGS of different micro dissections of tumor reveal intratumoral hetergenity

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cancer stem cells

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clonal heterogeneity histopathology is diverse, different differentiations, prolfieration varies, vascularity varies, inflammation and invasiveness varies special subcless of cell- cancer stem cells functionally able to start new tumors in other hosts have markers that are expressed on normal stem cells

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EGRF inhibitors

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treatment for sustaining proliferative signaling

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cyclin dependent kinase inhibitors

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treatment for evading growth suppressors

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immune activating anti CTLA4 mAb

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treatment for avoiding immune destruction

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telomerase inhibitos

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treatment for enabling replicative immortality

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selective anti inflammatory drugs

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treatment for tumor promoting inflammation

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inhibitors of HGF/c-Met

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treatment for activating invasion and metastasis

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inhibitors of VEGF signaling

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treatment for inducing angiogenesis

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PARP inhibitors

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genome instability and mutation

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Proapoptotic BH3 mimetics

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treatment for resisting cell death

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aerobic glycolysis inhibitors

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deregulating cellular energetics

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real time based somatic mutation detections

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KRAS, EGRF, BRAF, JAK2

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sanger sequencing based somatic mutation detection

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c-KIT, Braf, PDGF

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RNA based quantitative method with IS-MMR

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BCR-ABL Mbcr (P120) IS-MMR

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Fragmental analysis

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MSI identity index

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next generation sequencing

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cancer panel for hotspots (248 genes) T cell receptor clonality

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KRAS testing for colon cancer

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35% of metastatic CRC patients have mutations in the KRAS gene if mutations in codons 12 or 13 exist in metastatic tumor, they will not respond to cetuximab or panitumamab very expensive drugs, 3-4 month extension in life for wild type KRAS and anti-EGRF therapy

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EGFR and ALK testing

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lung cancer is the leading cause of cancer death in the US EGFR mutations predict who will respond to therapy (gefitinib and erlotinib-ATP binding inhibitors to EGFR) gene rearrangements for ALK determined by FISH will predict who wil respond to crizotinib

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EML4-ALK test in non small cell lung cancer

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non smokers, younger age, 3-5% of NSCLC, solid pattern adenocarcinomas, signet ring cells rearrangement caused by inversion in chromosome 2 all ELM4-ALK positive NSCLC are negative for EGFR ELM4-ALK translocation can be detected by FISH or molecular oral ALK4 receptor kinase inhibitor

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ERB1, HER1

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chromosome 7p12, a receptor tyrosine kinase, activation can result from protein overexpression, increased gene copy #, genetic mutations

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EGFR inhibitors

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small molecule inhibitors of EGFR getfitinib, erlotinib, competitive inhibitors of ATP binding at the active site of EGFR early clinical data showed that 10% of patients with NSCLC responded responders harbored specific mutations in the EGFR gene FDA approved for patients with advanced NSCLC have failed to respond to conventional chemo

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