Cancer Pathways
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Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
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Cancer Pathways
- 2. Cellular Signalling Pathway • Cells receive information from many different growth factor receptors and from cell-matrix and cell-cell contacts. • Cellular signaling pathways are not isolated from each other but are interconnected to form complex signaling networks • They must then integrate this information to regulate diverse processes, such as protein synthesis and cell growth, motility, cell architecture and polarity, differentiation, and programmed cell death.
- 3. Cellular Signalling Pathway • The same signaling molecules are used to control different processes within different signaling complexes or at different intracellular locations. • Moreover, signaling pathways could generate different outcomes in different cell types. • The intricacy of cellular signaling networks has major implications on our understanding of tumor cell behavior and our ability to use this knowledge for cancer therapy
- 4. Most Common Signaling Pathways
- 5. But actually the big picture much more complicated, interconnected and looks more like this !!
- 6. Nature Reviews designed the network as a Subway map; stops & lines leading to main stations Subway map designed by Claudia Bentley. Web
- 8. Cell Cycle
- 9. Two classes of regulatory proteins: 1) Cyclins: 2) Cyclin Dependant Kinases (CDKs)
- 10. Signalling pathways • Mutations in components of signaling pathways that control cell growth underlie tumour initiation • Ras, PI(3)K and mTOR are 3 signaling pathways that form an intersecting biochemical network. When mutated, these drive unrestricted cell growth. • Ultimately, these pathways drive tumorigenesis through the coordinated phosphorylation of proteins that directly regulate protein synthesis, cell-cycle progression and metabolism, and of transcription factors that regulate expression of genes involved in these processes
- 13. The Ras pathway • The name 'Ras' is an abbreviation of 'Rat sarcoma' • RAS is a family of GTPases that are activated by a wide range of cell-surface molecules • 3 isoforms : KRAS, NRAS, HRAS
- 14. The Ras pathway
- 16. The importance of this pathway is that multiple signals are funneled into MEK and ERK kinases (this pathway), allowing a nodal point for therapeutic targeting. It is is like a bottle neck where therapy can be targetted
- 17. The Ras/RAF/MAP kinase pathway • Upstream components of the pathway, such as the RAS and RAF are potent oncogenes. In cooperation with other events, can lead to profound changes , transforming normal cells into fully malignant . • Components of this pathway are under intense investigation as possible targets for anti-cancer therapeutics. • Mutated Ras is associated with ∼20−30% of all human cancers are often not responsive to established therapies • Resulting in a staggering 3 million new cancers diagnosed worldwide each year with RAS mutations.
- 18. RAS mutations • In particular, K-Ras, the most frequently mutated Ras isoform, is considered one of the most important but 'undruggable' targets in cancer research. • Despite intense efforts in pharmaceutical industry and academia, a therapeutic grip on oncogenic Ras proteins has remained elusive.
- 19. RAS mutations • Described in both hematologic and solid-tumor malignancies. • Different cancers (based on cell type of origin) show a propensity to mutate different RAS isoforms. – KRAS is the dominantly mutated isoform in colorectal and lung cancers – NRAS mutations dominate in hematologic malignancies and melanoma • Cancers with the most frequent RAS mutations are pancreatic cancer (90%), colorectal cancer (40%), non–small cell lung cancer (30%), bladder cancer (30%), peritoneal cancer (30%), cholangiocarcinoma (25%), and melanoma (15%). • In contrast, lymphomas, acute lymphoblastic leukemia, hepatocellular carcinoma, osteosarcoma, and prostate cancer less commonly contain RAS mutations.
- 20. RAF mutations • RAF kinases have 3 isoforms: BRAF, CRAF, ARAF • Identifying mutations in BRAF in human cancer has opened up profound new therapeutic opportunities for the management of cancer. • 6% of human cancers contain activating mutations in BRAF that result in more than 500,000 new cases of BRAF-mutated cancer diagnosed worldwide each year. • Similar to RAS mutations, BRAF mutations are profoundly oncogenic in cooperation with other genetic events and are capable of fully transforming normal cells.
- 21. BRAF mutations • The most common mutation in BRAF by far is the substitution of valine 600 by glutamic acid (V600E), which accounts for – more than 85% of the BRAF mutations in melanoma, – more than 50% of the mutations in non-small cell lung cancer – more than 95% of mutations in colorectal cancer, cholangiocarcinoma, and hairy-cell leukemia. • Just as RAS-mutated cells, BRAF mutation, are dependent on MEK and, by inference, ERK signaling for cell survival and proliferation. • MEK inhibitor: trametinib or dacarbazine (downstream) • BRAF inhibitors: vemurafenib, dabrafenib (upstream) • LGX818 F
- 25. PI3K/AKT/mTOR pathway • The PI3K/AKT/MTOR pathway is an intracellular signalling pathway important in apoptosis and hence cancer(e.g. breast cancer and non-small-cell lung cancer) and longevity. • The PI3K/AKT/MTOR pathway is activated by IGF1 and has a number of downstream effects which either promote protein synthesis or inhibit protein breakdown. • In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. • Cancer drugs trials aim to inhibit this signalling sequence at some point.
- 26. Combination of PI3K and MEK inhibitory drugs (in purple) to block the growth of lung tumors in a RAS-driven mouse transgenic mode Nature Medicine 14, 1315 - 1316 (2008)
- 27. mTOR • Mammalian Target of Rapamycin • Two distinct and mutually exclusive TOR complexes: – Raptor (the mTORC1 complex) : strongly inhibited by rapamycin (main focus of research) – Rictor (mTORC2) • Growth factors signal to mTORC1 complexes through both PI3(K)-AKT & Ras-ERK pathway. • Low nutrient availability (for example, low glucose or hypoxia) inhibits mTORC1
- 28. PI3K/AKT/mTOR pathway PI3 K : mutationally Red activated in cancer : mutationally Green inhibited in cancer
- 29. : mutationally activated in cancer : mutationally inhibited in cancer Cell growth, Gycolysis and Angiogenesis Red Green
- 30. • These findings have strong implications for cancer therapeutic strategies. • Rapamycin-based mTOR inhibitors • Inhibitors of PI(3)K–AKT signaling • Prolonged use of an inhibitor of a certain pathway (e.g. Rapamycin) could lead to enhanced activation of another pathway (PI3K). Thus combinations of drugs may be useful to avoid bypass routes
Notas del editor
- These are the 17 most common signalling pathways. We will go through some of them today. They begin with a stimulus at a receptor which triggers a pathway (usu a series of phosphorylations) ending in effectors leading to a cellular response Of course the big picture is not this simple becoz as we said earlier, cellular pathways are not isolated but interconnected to form a complex network Adenyl Cyclase -Cyclic AMP Cyclic ADP-ribose (cADPR) and nicotinic acid–adenine dinucleotide phosphate (NAADP) Voltage-operated channels (VOCs) Receptor-operated channels (ROCs) phospholipase C (PLC) to hydrolyse PtdIns 4,5P2 (PIP2): PtdIns 3-kinase Nitric oxide (NO) signaling Redox signaling: Mitogen-activated protein kinase (MAPK) signaling (RAS) Nuclear factor κB (NF-κB) signaling pathway: Phospholipase D (PLD) signaling pathway Sphingomyelin signaling pathway Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway Smad signaling pathway & TGF-B Wnt signaling pathways: Hedgehog signaling pathway: Notch signaling pathway: Endoplasmic reticulum (ER) stress signaling: AMP signaling pathway:
- So it looks more like this !! Stimuli start at cell membrane and trigger pathways which intersect & converge into major destinations (cellular responses) : proliferation, apoptosis, angiogenisis, repair of genes, differentiation
- Nature Reviews designed the network as a Subway or Metro map consisting of stops and lines as pathways all leading to main stations (major destinations) as cell cycle, proliferation, replicative life span
- Since we mentioned the cell cycle, this is a quick refresher of cell cycle components & regulators
- CC consists of 3 main phases : G1 , S , G2 then a phase of mitosis In Gi phase, the cell may choose to go into resting state G0 or continue in the cycle There are 3 checkpoints in the CC which are a sort of Quality Control tool to ensure that all cycle steps have been properly completed (marked in red). If the events are not going as planned, the cycle will not continue. Several tumour-suppressor proteins monitor intrinsic and extrinsic signals and integrate these inputs to decide whether the cell should remain in a quiescent state or enter into the cycle of active growth and division. There are 3 checkpoints : DNA synthesis, Mitosis, Cell growth
- The cyclins are a family of proteins whose concentration increases and decreases throughout the cell cycle. - The cyclins turn on, at the appropriate time, different cyclin-dependent protein kinases (CDKs) that phosphorylate substrates essential for progression through the cell cycle. - They are regulatory proteins with no catalytic activity. Cyclins are synthesized at specific steps of the cell cycle in response to various molecular signals. ) Cyclin Dependant Kinases (CDKs): - They have catalytic activity, but they are inactive in the absence of cyclins. - CDKs are present in constant concentrations during the cell cycle, although their state of activation varies.
- So it looks more like this !! Stimuli start at cell membrane and trigger pathways which intersect & converge into major destinations (cellular responses) : proliferation, apoptosis, angiogenisis, repair of genes, differentiation
- This is a close up into the 3 pathways we will be discussing We will take a look at RAS, then PI3 Kinase then mTOR pathways. As we said these signalling pathways form an intersecting biochemical network that if mutated, drive unrestricted cell growth
- The binding of a growth factor to an RTK activates Ras Ras act as a molecular switch, turning on downstream RAF protein kinases (BRAF, CRAF, and ARAF). The dominant substrates of RAF kinases are the MAPK/ERK kinases, MEK1, and MEK2. (translocated into nucleus) Their main substrate extracellular signal–regulated kinase (ERK). Activation of ERK generates extensive changes in gene expression mediated by transcription factors that control cell cycle progression, differentiation, protein synthesis, metabolism, cell survival, cell migration, and invasion and senescence (many of the hallmarks of cancer)
- RAS has a number of effectors as we can see here : all resulting in cellular responses leading to Proliferation & Evading apoptosis The pathway which we just discussed is RAS/RAF/MAP kinase/ERK pathway (in green) which specifically leads to change in gene expression of transcription factors that control cell cycle progression. Ras act as a molecular switch, turning on downstream RAF protein kinases (BRAF, CRAF, and ARAF). The dominant substrates of RAF kinases are the MAPK/ERK kinases, MEK1, and MEK2. (translocated into nucleus) Their main substrate extracellular signal–regulated kinase (ERK). Downstream of ERK, the pathway becomes more complex as ERK has many substrates. Activation of ERK generates extensive changes in gene expression mediated by transcription factors that control cell cycle progression, differentiation, protein synthesis, metabolism, cell survival, cell migration, and invasion and senescence (many of the hallmarks of cancer)
- The importance of this pathway is that multiple signals are funneled into MEK and ERK kinases (this pathway), allowing a nodal point for therapeutic targeting. It is is like a bottle neck where therapy can be targetted
- sequencing, denaturing gradient gel electrophoresis (DGGE), denaturing high-performance liquid chromatography (DHPLC), array or strip assay (allele-specific oligonucleotide hybridization), allele-specific polymerase chain reaction (PCR), and amplification refractory mutation system (ARMS)
- Next step in Pathway is RAF kinases
- First, as previous, events start by Growth factor binding to a RTK to activate PI3 K Notice that RAS activation can also lead to activation of PI3K, indicating that these pathways are interconnected at several levels. PI3K catalyzes the production of a lipid second messenger that helps to activate Akt. Once active, Akt can control many key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle. The PI3K pathway may be overactive because PTEN is faulty or deficient (a lipid phosphatase) in yellow also results in activation of this pathway, and inherited loss of PTEN confers susceptibility to many types of cancer Finally, note that Akt stimulates mTOr which is our next stop today.
- PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control many key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle. The PI3K pathway may be overactive because PTEN is faulty or deficient (a lipid phosphatase) also results in activation of this pathway, and inherited loss of PTEN confers susceptibility to many types of cancer
- Signals that inhibit TSC2, and thus activate mTORC1, include the kinases ERK and AKT, all by phosphorylation TSC2 tumour suppressor, tuberin, is mutated in a familial tumour syndrome called tuberous sclerosis complex (TSC). TSC patients are predisposed to widespread benign tumours termed hamartomas in kidney, lung, brain and skin. Loss of TSC2 results in raptor-mTOR complex activation through binding to Rheb activation, leading to tumour development. mTOR regulates the assembly of translation-initiation complexes thus controlling specific cell growth regulators, including the HIF-1α (hypoxiainducible factor-1α) transcription factor, which in turn drive diverse processes including cell growth, glycolysis and angiogenesis, all contributing to enhanced tumorigenesis. Interestingly, HIF-1α protein degradation is independently negatively regulated by the von Hippel–Lindau (VHL) tumour suppressor, providing another link between this pathway and cancer, and another genetic setting in tumours in which mTOR inhibitors may prove efficacious.
- 1- Cell cycle : Putting the breaks on cell cycle !! Cyclins & CDKs Two tumour-suppressor pathways that block progression through cell cycle : Retinoblastoma (RB) pathway p53 pathway are inactivated in most, if not all, cancer cells. Transforming growth factor-b (TGF-b) pathway The WNT-Frizzled signalling pathway Not everything is shown in this diagram ! 2- Apoptosis : Tumour growth: increased cell division or decreased tumour-cell attrition. Most cancer cells acquire resistance to the various mechanisms that lead to programmed cell death. Presented here in a simplified form, pathways converge on a series of intracellular proteases that ultimately lead to cell death. Cancer cells : Blocking pro-apoptotic pathways: inactivating the p53 tumour-suppressor pathway: p53 (transcription factor) is targeted for degradation in the proteasome by MDM2, an oncogenic ubiquitin ligase5. In turn, MDM2 is inhibited by ARF (also known as p14 in humans). Upregulate anti-apoptotic pathways. The growth-factor-mediated activation of (PI3K) 3- Proliferative : Extracellular signals consist of a linear series of signalling molecules that link the cell surface to intracellular machinery that affects cell growth and division. Activating mutations in many of these genes are oncogenic and serve to liberate cancer cells from these normal homeostatic mechanisms, allowing self-sufficient proliferation. Many growth-factor signalling pathways begin with the activation of a RTK by a growth factor or sometimes GPCRs RAS pathway (PI3K) pathway 4- Mobilization of resources : Changes in gene expression and protein metabolism. activation of these pathways to mobilize the cellular resources necessary for the cancer-cell phenotype. E.g. activation of metabolic programmes that confer specific advantages to a continuously dividing cancer cell. Ribosome biosynthesis, expression of differentiation-associated antigens, enzymes involved in nutrient metabolism and enzymes that regulate oxidative potential. For example, blocking apoptotic pathways, PI3K/AKT/PTEN pathway activating biosynthetic pathways. PP2A and the serine/threonine kinase TOR are also thought to be involved in this biosynthetic route; both of these can activate ribosomal S6 kinase (RSK), an important regulator of ribosome assembly. PP2A also activates eukaryotic initiation factor 4E (eIF4E), a protein that is involved in ribosome biogenesis The identification of gene mutation or loss of each of these molecules in human cancers indicates that these biosynthetic pathways have important functions in cancer pathogenesis 5- Routes under construction : Angiogenesis Metastasis: ? TGF-b, hepatocyte growth factor (scatter factor) and the loss of adhesion molecules such as E-cadherin Tumour-stroma interactions: ? MMP or attracting immune cells Tissue-specific pathways ? WNT/ b-catenin pathway in colorectal cancer ( mutation of the APC tumour-suppressor gene) . Germ-line mutation of particular tumour-suppressor genes, such as RB or BRCA1, confers increased susceptibility to retinoblastoma or breast and ovarian cancer, respectively, only , not other types of cancer. Regulation of genomic stability ionizing radiation ( a DNA-damaging agent ) activates p53-mediated cell-cycle checkpoints and DNA repair. Aneuploidy can arise by dysregulation of a spindle checkpoint or by loss of telomere integrity. Accumulation of small mutations as a result of defects in the machinery that is responsible for DNA mismatch repair. Immune surveillance Does the immune system carry out continuous surveillance to prevent tumours formation? Only a small subset of human tumours arise in immunodeficient individuals (tumours that are associated with viral infections) Paradoxically, the inflammatory milieu that develops at sites of strong immune responses might contribute positively to tumour progression, as many of the cytokines released can trigger proliferation and survival of tumour cells, as well as angiogenesis