Flashcards in Hallmarks Deck (69):
The Big 8 - Hallmarks of Cancer
1) Avoiding immune destruction2) Evading growth suppressors3) Enabling replicative immortality4) Activating invasion and metastasis5) Inducing angiogenesis6) Resisting cell death7) De-regulating cellular energetics8) Sustaining proliferative signaling
A governor of proliferation and differentiationA key negative regulator of the G1-S transitionCancer inactivates it => two possible ways:1) loss-of-function mutation involving both Rb alleles2) A shift from the active, hypo-phosphorylated state to the inactive, hyper-phosphorylated state by gain-of-function mutations that up-regulate CDK/cyclin D activity or by loss-of-function mutations that inhibit CDK inhibitors
Hypo-phosphorylated Rb in complex with E2F transcription factor means what for the cell cycle?
This complex inhibits transcription of genes whose products are required for the S phase of the cell cycle.
Phosphorylation of Rb: process and consequence
Rb is phosphorylated by cyclin D/CDK4, cyclin D/CDK6, and cyclinE/CDK2 complexes. When these complexes phosphorylate Rb, they are inhibiting it from keeping hold of E2F.Upon phosphorylation, Rb releases the E2F transcription factor.E2F activates the transcription of S-phase genes.
Who inhibits phosphorylation of Rb?
Cyclin-dependent kinase inhibitors phosphorylate Rb indirectly because CDKIs inhibit cyclin-CDK complexes, which are the complexes that phosphorylate RB.
What does an active Rb look like, and where is it found?
A active Rb is hypo-phosphorylated, attached to E2F, and found in quiescent cells.
What does an inactivate Rb look like, and where is it found?
An inactive Rb is hyper-phosphorylated, thanks to high levels of the cyclinD/CDK4, cyclinD/CDK6, and cyclinE/CD2 complexes (these complexes are up-regulated by growth factors). It has released the E2F transcription factor.It is found in cells passing through the G1/S cell cycle transition.
Growth factor signaling pathway vs. Growth inhibition signaling pathwayWhat does Rb have to do with these pathways?
Growth factors up-regulate the cyclins and CDKs required for transitioning through phases in the cell cycle, whereas growth inhibitors up-regulate CDKIs to stop progression through cell cycle phases. Rb is the point of integration of these opposing signals, making it the key regulator of cell cycle progression.
According to current cancer data, which molecules are typically mutated or affected in patients with cancer?
p16/INK4acyclin DCDK4RbEither these guys have mutations, or they are affected by an abnormal molecule upstream of them in the signaling pathway (meaning they're normal, but cannot be activated/deactivated due to the struggler ahead in line).
What can oncogenic viruses do to Rb?Example?
The viral protein can bind to Rb, functionally inhibiting it so that it can no longer act as a cell cycle inhibitor (it can no longer hold on to E2F because the virus took that spot, so E2F goes off and transcribes things needed for the S phase of the cell cycle).Example: HPV types express a protein called E7 that binds with higher affinity to Rb than E2F does, leading to a high risk for cervical carcinoma.
blue 52! blue 52! Who p53?
Ye ol' p53 is the guardian of the genome and the central monitor of stress in the cell.Activated by anoxia, inappropriate signaling by mutated oncoproteins, or DNA damageMany jobs: 1) Prevents propagation of genetically damaged cells2) Binds to DNA3) Arrests cell cycle for DNA repair4) Initiates apoptosis if repair impossibleHe lives only for half-life of 20 minutes and is killed by ubiquitin proteolysis.
Is p53 affected in patients with tumors? If so, how?
Yes, it most certainly can be affected; 70% of the time there is bi-allelic loss of p53.Example: HPV expresses E6 protein, which degrades p53 (recall there is also an E7 protein associated with HPV).
A tumor suppressor gene that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosisA gene that encodes p53.The most frequently mutated gene in cancer; found in 50% of cancersMutation is not usually inherited, so it's found in somatic cells, with both alleles of the gene mutated.
The syndrome you have when you DO end up inheriting a mutated TP53 allele.You have a 25-fold greater chance of getting cancer because you're now just one mutation away from inactivating TP53
An inhibitor of p53. Phosphorylation of p53 releases it from the clutches of MDM2It is over-expressed in 33% of malignancies. It stimulates the degradation of p53.
E6 and E7
Proteins expressed by HPV that bind to RB with higher affinity than E2F, causing inactivation of RB and therefore progression of cell cycle to S phase, as E2F is now free to transcribe the proteins required.
p53 is a transcription factor. The key target genes that execute the functions of p53 are not really defined, but tend to fall in three categories:p53 also affects genes that encode two kinds of regulator RNA. What are they?
KEY TARGET GENES1) those that cause cell cycle arrest2) those that cause apoptosis3) those that enhance catabolic metabolism or inhibit anabolic metabolismREGULATORY RNA1) micro-RNA (mIRs)2) long intervening noncoding RNAs (LINC RNAs)These help to coordinate the p53-dependent cellular response to stress.
How is DNA damage sensed?
Damage is sensed by complexes containing the kinases of the ATM/ATR family. The kinases phosphorylate p53, freeing it from inhibitors such as MDM2.Active p53 up-regulates p21, a CDKI that inhibits cell cycle progression to the S-phase, standing guard at the G1/S checkpoint.DNA repair can now occur during the pause in cell cycle progression. Hopefully, for the cell's sake. If no, then bye-bye cell, 'ello apoptosis!
Von Hippel Lindau
A gene product that causes ubiquination and degradation of hypoxia inducible transcription factor-1.Result: Increased PDGF and VEGF => tumor angiogenesis.
Adenomatous polyposis coli (APC) and consequence of its germline loss-of-function mutation
A tumor suppressor that down-regulates growth-promoting signaling pathways.Molecular Consequence: loss of APC causes cells to behave as if they're continuously stimulated by WNT.Clinical Mutation Consequence: Familial adenomatous polyposis, an autosomal dominant disorder in which people born with one mutant allele develop thousands of polyps in the colon, one or more of which will invariably undergo mutant transformation, giving rise to colon cancer IF the other allele also ends up suffering a mutation.
Does APC really have anything to do with colorectal carcinomas?
Fo sho'. 70% of non-familial colorectal carcinomas and sporadic adenomas show acquired defects in both APC genes; thus, APC loss-of-function mutations are important in the formation of colonic tumors.
General relationship between Wnt/Frizzled, APC, and B-catenin
Wnt/Frizzled sends a signal to APCAPC responds by failing to form a proteosomal degradation complex to degrade B-catenin.B-catenin heads to nucleus, forms a complex with DNA binding factor TCF, and they together promote colonic epithelial cell growth
Consequence of loss of APC or lack of Wnt signaling to APC
If Wnt does not send signals to APC, APC forms a complex that degrades B-catenin. B-catenin can no longer promote colonic epithelial cell growth. If lack APC, as many colorectal patients do, APC is not available to degrade B-catenin, and unfettered proliferation of colonic epithelial cell growth results. Dysregulation of APC plays a role in cancers other than colorectal.
A proto-oncoprotein that plays a role in colonic epithelial cell growth.A gain-of-function mutation could lead to hepatoblastoma or hepatocellular carcinomas.If APC is lost (it is upstream of B-catenin in signaling process), then it can also enjoy unfettered cell proliferation.
The relationship between B-catenin and E-cadherin. How can their relationship lead to cancer?
E-cadherin maintains cellular adhesiveness. B-catenin is bound to E-cadherin. Their association is disrupted upon injury or trauma. In response, B-catenin heads to the nucleus, where it stimulates genes that promote proliferation that help with wound repair. Once repair is finished, B-catenin re-associates with E-cadherin and therefore remains sequestered in the cell membrane; this means these cells are "contact-inhibited". In the words of Dr. Nichols, "This is good."Cancer: Loss-of-contact inhibition or mutation of the E-cadherin/B-catenin complex can lead to cancer. Loss of E-cadherin (and therefore cell adhesion) also allows easy disaggregation of cells, which means that they can then head out to another site and invade (or invade locally).
What is the consequence of reduced cell surface expression of E-cadherin?
Carcinoma, especially in esophagus, colon, breast, ovary, and prostate.
The E-cadherin geneA germline loss-of-function mutation in this gene causes familial gastric carcinoma.
TGF-B: Normal and Cancer
Normally an inhibitor of proliferation1) Bind TGF-B receptors I and II, causing them to dimerize2) Dimerization initials intracellular signals (involving the SMAD family of proteins) that turn ON anti-proliferative genes and turn OFF proliferative genes.3)T These changes result in hypo-phosphorylation of Rb, causing it to hang on to E2F. …But also a double-edged sword that can promote or prevent tumor growth1) Loss-of-function mutation in the TGF-B signaling pathway2) Mutations in TGF-B II receptor that lead to cancers of the colon, stomach, and endometrium3) Mutational inactivation of SMAD4 leads to pancreatic cancer4) Loss of TGF-B mediated growth inhibition via mutations causing loss of p21 or sustained expression of MYC (MYC is a growth promoter)5) Sometimes preserved elements of TGF-B can allow for immune evasion and angiogenesis.
A membrane-associated phosphatase that acts as a tumor suppressor by serving as a brake on the P13K/AKT arm of the receptor tyrosine kinase pathway.Gene function can be lost through deletion, deleterious point mutations, or epigenetic silencing; seen notoriously in endometrial carcinoma.Can be mutated, causing Cowden syndrome
An autosomal dominant disorder marked by frequent benign growths, such as skin appendage tumors, as well as an increased incidence of epithelial cancers, particularly of the breast, endometrium, and thyroid.
This locus encodes:1) p16/INK4a, a CDKI that augments Rb function (allows it to hold tight to T2F)2) ARF, which stabilizes p53
This gene encodes neurofibromin 1, a GTPase that acts as a negative regulator of Ras (recall that activation of Ras leads to signaling that allows for gene transcription and that Ras is active only when GTP is bound)Germline loss-of-function mutations cause Neurofibromatosis Type I
This gene encodes neurofibromin 2, a cytoskeletal protein involved in contact inhibition (recall the relationship of E-cadherin and B-catenin as an example of a contact inhibition relationship).Germline loss-of-function mutation leads to Neurofibromatosis Type II.
This gene encodes a transcription factor that is required for normal development of genitourinary tissuesGermline loss-of-function mutations are associated with a pediatric kidney cancer called Wilms tumor.
This gene encodes a membrane receptor that is a negative regulator of the Hedgehog signaling pathway.Germline loss-of-function mutations cause Gorlin syndromeAcquired bi-allelic loss-of-function mutations of PTCH1 are seen frequently in basal cell carcinomas and medulloblastomas.
An autosomal dominant disorder associated with high risk of basal cell carcinoma and medulloblastomas.Caused by a germline loss-of-function mutation in PTCH1.
A pediatric kidney cancer caused by a germline loss-of-function mutation in WT1.
Neurofibromatosis I and II
Caused by germline loss-of-function mutations in NF1 and NF2
Cancer: Evasion of Apoptosis
Apoptosis can be initiated either through extrinsic or intrinsic pathways, and abnormalities are found in both pathways in cancer cells, though intrinsic is most common.
General ways cancer has limitless replicative potential
1) Some cells in cancer are always stem-like, either because an actual stem cell is affected, or because a genetic lesion imparts a stem-like ability.2) Cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase, which act together to convey limitless replicative potential.
Hypoxia, Angiogenesis, and Cancer
1) A tumor needs to be vascularized in order to survive. 2) Hypoxia of the cancer triggers angiogenesis via HIF-1-alpha, which interacts with VEGF. (This means that many cancers are treated, though not cured, with VEGF inhibitors)3) p53 regulates angiogenesis by inducing the synthesis of angiogenesis inhibitor thrombospondin-1
Angiogenesis inhibitor thrombospondin-1
Produced by p53 in an attempt to control angiogenesis of tumors.
Signaling dudes that up-regulate VEGF expression
RASMYCMAPKThese all stimulate angiogenesis.
______________ has displaced squamous cell carcinoma as the most common type.
Adenocarcinoma.1) Seen in higher percentages of non-smokers, women, and Asians.2) Seen in higher percentages of peripheral lung cancer.Why? Theorized that pollution plays a role. Also that cigarettes filter only large particles that typically would get stuck in the central airway, allowing the smaller ones to escape to the periphery of the lungs.
Bronchioloalveolar carcinoma (BAC)
The name for pulmonary adenocarcinoma in situ.Recall that carcinoma in situ means that the tissue has all of the cytologic features of malignancy without visible invasion.
Atypical adenomatous hyperplasia (AAH)
The precursor to PULMONARY adenocarcinoma(The same thing as "dysplasia")
Process:1) An alteration in intracellular adhesion molecules (e.g. E-cadherin) allows dissociation of cancer cells from each other2) Carcinoma breaches the basement membrane either by secreting their own proteolytic enzymes or getting other cells to do so3) Then, tumor cells attach to ECM proteins; when MMPs cleave collagen IV and laminin, new sites that bind to tumor cells appear and stimulate migration4) Tumors secrete cytokines like autocrine motility factors that direct migration.
Mediate the HOMOTYPIC adhesion of epithelial cells and relay signals between cells to maintain contact inhibition and prevent abnormal growth
Proteases that aid in degradation of the basement membrane when a cancer cell is attempting to escape
MMPs (matrix metallo-proteinases), cathepsin D, and urokinase plasminogen activator
A gelatinase that cleaves Type IV collagen of the epithelial and vascular basement membrane and stimulates the release of VEGF from ECM-sequestered pools.
Stromal cells and metastasis
Stromal cells can produce paracrine effectors to initiate cell motility. E.g. Hepatocyte growth factor/scatter factor binds to MET on tumor cells, helping with motility.
Tumor cell behavior in circulation, and their motivation for said behavior
Tumor cells aggregate in clumps because of their homotypic adhesions and because of their ability to bind to blood cells, particularly platelets. They can also cause formation of emboli by binding coagulation factors.Motivation: Formation of platelet-tumor aggregates may enhance tumor cell survival and implantability.
Normally used by T-cells to bind to hyaluronate on HEVs in order to extravasate into lymphoid tissuesUsed by solid tumors to enhance their spread to lymph nodes and other metastatic sties
Causes for characteristic patterns of metastases
1) Drainage pathways2) Organ tropismThe site at which circulating tumor cells leave capillaries is related to the anatomic location and vascular drainage of the primary tumor, as well as the tropism of particular tumors for specific tissues.
Metastatic organ tropism: Its determinants
Various organs will express varying concentrations of endothelial cell ligands for adhesion moleculesFor example, CXCR4 and CCR7 chemokines are receptors heavily utilized by breast cancers, whereas other chemokines might encourage development of lung cancer
Where do prostatic carcinomas prefer to spread?
Where do cell carcinomas prefer to spread?
Liver and adrenals
Where to neuroblastomas prefer to go?
Liver and bones
How do cancer cells turn a site into their new home?
They can secrete cytokines, growth factors, and ECM molecules that on resident stromal cells, which in turn make the site habitable for the cancer cell.
How does breast cancer spread to bone?
1) Breast cancer cells secrete parathyroid hormone-related protein (PTHRP)2) PTHRP stimulates osteoblasts to make RANK ligand (RANKL)3) RANKL activates osteoclasts, which degrade the bone matrix and release growth factors embedded within it, like IGF and TGF-B
SNAIL and TWIST
Metastasis oncogenes that encode transcription factors whose primary function is to promote epithelial-to-mesenchymal transition (EMT). One way they achieve this is through acting as repressors that down-regulate E-cadherin expression
How does a cancer cell become pro-migratory?
It down-regulates epithelial markers like E-cadherin and up-regulates mesenchymal markers like vimentin.
Seen mostly in breast cancerStands for "epithelial-to-mesenchymal transition"Key event in EMT is the loss of E-cadherin, which greatly helps with migration of tumor cells to a secondary site.
Hereditary nonpolyposis colon cancer (HNPCC)
An autosomal dominant disorder characterized by familial carcinomas of the colonOccurs due to defects in a family of genes that encode proteins that engage in DNA mismatch repairAffected individuals inherit one abnormal copy of mismatch repair gene, then cells acquire a loss-of-function mutation that knocks out the other allele. Mutations slowly mount that could end up activating proto-oncogenes or inactivate tumor suppressor genes, in time leading to cancer
Defective DNA-repair genes
These have the same mode of inheritance as tumor suppressor genes (in the way that a person is born with one good allele and one bad), but they affect cell growth only indirectly by allowing mutations to accumulate.They are enablers of cancer.
Tandem repeats of 1-6 nucleotides are found throughout the genome. In normal people, that length parameter remains constant.In affected individuals, the length does not remain constant in some cells. These abnormal cells create alleles not found in unaffected cells of the same patient.
Mismatch repair genes involved in pathogenesis of HNPCC
Germline mutations in MSH2 and MLH genes
Cancer genes mutated in HNPCC
1) Genes encoding TGF-beta receptor II2) TCF component of the B-catenin pathway3) BAX