Origins I TBL 7

gain of function mutations in D cyclin genes and CDK4, oncogenes that promote G1/S progression (3 D cyclin genes dysregulated by mutations in cancer; including translocations or amplification of CDK4 gene) loss of function mutations in tumor/suppressor genes that inhibit G1/S progression (CDKIs that inhibit cyclin D/CDK complexes are mutated or silenced)

2 major cancer associated mutations that affects G1/S checkpoint

1. DNA damage and hypoxia (key initiators of p53 activation following DNA damage or hypoxia are 2 related PK's-ATM and ATR-once triggered, both stimulate phosphorylation of proteins, including p53 and MDM2, allowing p53 to accumulate) 2. oncogenic stress (activation of oncoproteins such as RAS leads to sustained, supraphysiologic signaling through pro growth pathways such as MAPK and P13K/AKt pathways, these signals create cellular stress and lead to increased expression of p14/ARE which binds MDM2 and displaces p53 allowing p53 levels to rise in cell)

2 mechanisms of how p53 is released from inhibitory effects of MDM2

loss of function mutations involving both RB alleles shift from active hypOphosphorylated state to inactive hypERphosphorylated state by gain of function mutations that upregulate CDK/cyclin D activity or by loss of function mutations that abrogate the activity of CDK inhibitors

2 ways RB function may be compromised

Li-Fraumeni syndrome

25x greater chance of developing a malignant tumor by age 50 than the general population; spectrum of tumors that develop in persons with this is quite varied; often develop cancers at younger ages and are more likely to suffer from multiple primary tumors of varying types than are normal individuals

growth promoting proto-oncogenes, growth inhibiting tumor suppressor genes, genes that regulate programmed cell death, and genes involved in DNA repair

4 classes of normal regulatory genes that are principal targets of cancer causing mutations

1. self sufficiency in growth signals (capacity to proliferate without external stimuli-result of oncogene activation) 2. insensitivity to growth inhibitory signals (tumors may not respond to molecules that inhibit proliferation of normal cells-inactivation of tumor suppressor genes that encode factors of growth inhibitory pathways) 3. altered cellular metabolism (tumor cells switch to aerobic clycolysis-Warburg effect-enable synthesis of macromolecules and organelles needed for cell growth) 4. evasion of apoptosis 5. limitless replicative potential (unrestricted proliferative capacity) 6. sustained angiogensis 7. ability to invade and metastasize 8. ability to evade host immune response

8 fundamental changes in cell physiology which are considered hallmarks of cancer

products of mutated protooncogenes tumor suppressor genes overexpressed or aberrantly expressed proteins tumor antigens produced by oncogenic viruses oncofetal antigens altered glycolipids and glycoproteins cell type specific differentiation antigens

different classes of tumor antigens

ERBB2

encodes a different member of TK family, HER2; rather than being activated by point mutations, this gene is amplified in certain breast carcinomas, leading to overexpression of HER2 receptor and constitutive TK activity

WT1

encodes a transcription factor that is required for normal development of genitourinary tissues; germline loss of function mutations associated with Wilms tumor, a pediatric kidney cancer, similar mutations also found in sporadic Wilm's tumor

VHL

encodes component of ubiquitin ligase that is responsible for degradation of hypoxia induced factors, transcription factors that alter gene expression in response to hypoxia; germinline loss of function mutations cause von HIppel-Lindau syndrome, autosomal dominant disorder associated with a high risk of renal cell carcinoma and pheochromocytoma; acquired bialleclil loss of mutations are common in sporadic renal cell carcinoma

PTEN

encodes lipid phosphatase that is important negative regulator of P13K/AKT signaling; germline loss of funciton mutations associated with Cowden syndrome, autosomal dominant disorder associated with high risk of breast cancer; biallelic loss of function common in diverse cancers

PTCH1

encodes membrane receptor that is negative regulator of Hedgehog signaling pathway; germline loss of function mutations cause GOrlin syndrome, autosomal dominant disorder associated with a high risk of basil cell carcinoma and medulloblastoma

ERBB1

encodes the epidermal growth factor receptor ECFr which is involved by point mutations in certain cancers. several point mutations of this are found in subset of lung adenocarcinomas and can result in constitutive activation of ECFr tyrosine kinase

DNA methylation (silences gene expression) modifications of histones proteins that package DNA into chromatin

epigenetic aberrations like ___ also contribute to malignant properties of cancer cells; these mutations are passed to daughter cells but alterations may occur that result in changes in gene expression

angiogenesis

even if solid tumor possesses all of genetic aberrations required for malignant transformation, it cannot enlarge beyond 1-2mm in diameter unless it has capacity to induce ?

high levels of glucose uptake and increased conversion of glucose to lactose via glycolytic pathway Warburg effect (or aerobic glycolysis)

even in presence of ample oxygen, cancer cells demonstrate a distinctive form of cellular metabolism characterized by? what is this phenomenon called?

JAK2

example of type of mutation in which abrogation of function of negative regulatory domains that normally hold enzyme activity in check; this is a nonreceptor TK that participates in JAK/STAT signaling pathway which transduces mitogenic signals from growth factor and cytokine receptors that lack TK actibity. Activation of JAK/STAT alters expression of target genes that bind STAT transcription factors. Developement of inhibitors for this are being made for treating myeloproliferative disorders and has stimulated searches for activating mutations in other nonreceptor TKs

MYC proto oncogene

expressed in virtually all euk cells and belongs to immediate early response genes which are rapidly and transeintly induced by RAS/MAPK signaling following growth factor stimulation of quiescent cells; normally tightly controlled at level of transcription, translation and protein stability

relative lack of oxygen due to hypoxia stimulates factors that lead to proliferation of endothelial cells and growth of new vessels towards tumors mutations involving tumor suppressors and oncogenes tilt balance in favor of angiogenesis transcription of VEGF influenced by signals from RAS-MAP kinase and gain of function mutations in RAS and MYC

factors that influence local balance of angiogenic and antiangiogenic factors

tumor suppressor proteins

form a network of checkpoints that prevent uncontrolled growth; many are part of a regulatory network that recognizes genotoxic stress from any source and shuts down proliferation; another set seems to be involved in cell differentiation, causing cells to enter a postmitotic, differentiated pool without replicative potential ; these signals originate outside the cell and use receptors, signal transducers and nuclear transcription regulators to accomplish their effects and these form a portion of these networks thus these may function as transcription factors, cell cycle inhibitors, signal transduction molecules, and cell surface receptors, and regulators of cellular responses to DNA damage

platelet tumor aggregates

formation of ___ may enhance tumor cell survival and implantability

by serving as a focal point for large network of signals that sense cellular stress, primarily DNA damage but also shortened telomeres, hypoxia, ans tress caused by excessive pro growth signaling

frequent loss of p53 funciton in human tumors reflects its critical role in prevention of cancer development; how does p53 carry out this role? in non stressed cells, p53 is kept at bay through its association with MDM2 but in stressed cells, p53 is released from inhibitory effects of MDM2

deletions

frequently cause loss of tumor suppressor gene function and occasionally activate proto-oncogenes

familial neurofibromatosis type 1

gain of function mutations of RAS should be mimicked by loss of function mutations of GAPs; disabling mutations of neurofibromin 1, a GAP encoded by NF-1 gene, is associated with inherited ___ which is an example of tumor suppressor gene that acts through negative regulation of RAS signalign

cell-mediated mechanisms tumor antigens

antitumor activity is mediated by ___ mechanisms (mostly). ___ are presented on cell surface by MHC class I molecules and are recognized by CD8+CTLs

chromosomal translocation

any type of chromosomal rearrangement can activate proto-oncogenes but ___ is the most common mechanism to date (fusion gene of promoter or enhancer substitution leading to overexpression of proto-oncogene)

stem cell like

at least some cells in all cancers must be ___; these cells are sometimes referred to as cancer stem cells and 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; cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase, which act together to convey limitless replicative potential

APC

gatekeeper of colonic neoplasia; member of class of tumor suppressors that function by downregulating growth promoting signaling pathways; germline loss of function mutations involvind adenomatous polyposis, an ausomal dominant disorder in which individuals born with one mutant allele develop thousands of adenomatous polyps in colon during teens or 20s; component of WNT signaling pathway which has a major role in controlling cell fate, adhesion, and cell polarity during embryonic development; major function is to hold beta catenin activity in check

oncogenes proto-oncogenes

genes that promote autonomous cell growth in cancer cells; created by mutations in their unmutated cellular counterparts and encode proteins called oncoproteins that have ability to promote cell gwoth in absence of normal growth promoting signals their unmutated cellular counterparts are?

driver mutations

genetic aberrations that increase mutation rates are very common in cancers and expedite the acquisition of ___ that are required for transformation and subsequent tumor progression

genetic alterations to MYC itself, elevation in MYC levels by upstream components increases its transcription, etc, stabilizing it and allowing for constitutive signaling

how MYC can be deregulated in cancer

angiogenesis is controlled by a balance between angiogenesis promoters and inhibitors; in angiogenic tumors, balance is skewed in favor of promoters

how do growing tumors develop a blood supply?

1. mutations that were present in all tumor sites tested, which were presumably present in founding cell at moment of transformation 2. mutations that were unique to a subset of tumor sites which were likely acquired after transformation during outgrowth and spread of tumor (this can be used to create tumor family tree showing relationship of subclones)

how do we know that genetically distinct subclones really exist in any particular cancer?

clonal expansion of a single precursor cell that has incurred genetic damage DNA sequencing (point mutations) or chromosomal analyses (chromosomal translocations and copy number changes)

how is a tumor formed (general)? alterations in DNA are heritable, being passed to daughter cells and thus all cells within an individual tumor share same set of mutations present at moment of transformation; tumor specific mutations are identified by?

metabolic reprogramming is produced by signaling cascades downstream of growth factor receptors, the very same pathways that are deregulated by mutations in oncogenes and tumor suppressor genes in cancers; thus whereas in rapidly growing normal cells aerobic glycolysis ceases when tissue is no longer growing, in cancer cells, this reprogramming persists due to action of oncogenes and loss of tumor suppressor gene function

how is profound reprogramming of metabolism, the Warburg effect, triggered in growing normal and malignant cells?

selective outgrowth of antigen-negative variants loss or reduced expression of histocompatibility antigens immuno suppression mediated by expression of certain factors by tumor cells

how tumors may avoid immune system in immunocompetent patients

oncoproteins tumor suppressors

___ have been likened to accelerators that speed replication of cells and their DNA and ____ have been viewed as brakes that slow or arrest this process

aberrant DNA methylation, histone modifications

___ in cancer cells is responsible for silencing of some tumor suppressor genes while tumor specific changes in ___ may have far ranging effects on gene expression in cancer cells

receptor tyrosine kinases continuous mitogenic signals to cell, even in absence of growth factor in environment

a large number of oncogenes encode growth factor receptors, of which ___ are arguably the most important in cancer; recall these are transmembrane proteins with an EC ligand binding domain and a cytoplasmic tyrosine kinase domain; normally its activity is activated transiently by binding of a specific growth factor to EC domain, an event that induces a rapid change in receptor conformation to an active dimeric state; activated receptor then autophosphorylated tyrosine residues in its own IC tail and these modified residues serve as sites for recruitment of a number of signaling molecules, including RAS and P13K which have already been described as key players in this signaling; mutant receptors deliver?

RB

a major tumor suppressor; governor of proliferation, a key negative regulator of G1/S cell cycle transition, directly or indirectly inactivated in most human cancers; also controls cellular differentiation and exists in an active hypophophorylated state in quiescent cells and an innactive hyperphophorylated state in cells passing through G1/S cell cycle transition

mutations in genes that regulate apoptosis. In adults, cell deeath by apoptosis is a protective response to several pathologic conditions that might contribute to malignancy if cells remained viable

accumulation of neoplastic cells may result not only from activation of growth promoting oncogenes or inactivation of growth suppressing tumor suppressor genes, but also from?

gene rearrangements

activate other receptor TK's leading to constitutive TK activity

nucleus

all signal transduction pathways converge on ___ where expression of target genes that orchestrate cell's orderly advance through mitotic cycle is activated

E cadherin

cell adhesion molecule that plays an important role in contact mediated growth inhibition of epithelial cells and also binds and sequesters beta catenin, a signaling protein that functions in WNT pathway; loss can contribute to malignant phenotype by allowing easy disaggregation of cell which can then invade locally or metastasize

chromosomal abnormalities

certain ___ are highly associated with particular neoplasms and inevitably lead to the dysregulation of genes with an integral role in pahtogenesis of that tumor type

genomic instability and cancer promoting inflammation

considered enabliing characteristics because they promote cellular transformation and subsequent tumor progression

balanced translocations

contribute to carcinogenesis by overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity

loss of normal cell cycle control p16/INK4a, cyclin D, CDK4, RB

current paradigm is that ___ is central to malignant transformation and that at least one of 4 key regulators of cell cycle, ____, is dysregulated in the vast majority of human cancers; in cells that harbor mutations in any one of these other genes or in upstream factors that regulate their expression and function, RB may be functionally inactivated even if the RB gene itself is not mutated

complex interactions between cancer cells and normal stroma and are major causes of cancer related morbidity and mortality for tumor cells to emerge from a primary mass, enter blood vessels or lymphatics, and produce a secondary growth at a distant site, they must go through a series of steps that are inefficient and subject to a multitude of controls

invasion and metastasis are the results of? why is this process so inefficient?

mutation of E cadherin/beta catenin axis or other changes

loss of contact inhibition (in WNT and APC signaling) by mutation of ___ is a key characteristic of carcinomas

repair genes mutator phenotype

loss of function mutations affecting DNA ___ contribute to carcinogenesis indirectly by impairing ability of cell to recognize and repair nonlethal genetic damage in other genes; as a result, affected cells acquire mutations at an acclerated rate, a state referred to as? that is marked by genomic instability

risk of cancer is inherited as an autosomal dominant trait, tumors acquire a second hit in the sole normal tumor suppressor gene allele, and the same tumor suppressor gene is frequently mutated in sporadic tumors of the same type

major themes of study of familial retinoblastoma hold for other familial cancers:

excessive growth, local invasiveness, ability to form distant metastases

malignant neoplasms have several phenotypic attributes referred to as cancer hallmarks ___- which stem from genomic alterations that change the expression and function of key genes and thereby impart a maligant phenotype

apoptosis regulating genes

may acquire abnormalities that result in less death and therefore enhaced survival of cells; these include gain of function mutations in genes whose products supress apoptosis and loss of function mutations in genes whose products promote cell death

invasion of EC matrix and vascular dissemination, homing of tumor cells, and colonization

metastatic cascade is divided into 2 phases

BRAF

mutations in ___ have been detected in close to 100% of hairy cell leukemias, many melanomas, and benign nevi, and other neoplasms; is a serine/thre PK of MAPK family; like activating RAS mutations, activating mutations of this sitmlate each of downstream kinases and ultimately activate transcription factors

P13K

mutations of ___ are very common in certain cancers; this is a heterodimer comprised of regulatory subunit and catalytic subunit of which several tissue specific isoforms exist. Under normal circumstances, this is recruited by TK activation to plasma membrane associated signaling complexes and it activates a cascade of serine/threonine kinases including AKT

proto-oncogenes transform cells despite presence of a normal copy of same gene (thus oncogenes are dominant over normal counterparts)

mutations that activate ___ generally cuase excessive increase in one of more normal functions of encoded gene product or somteimes impart a new function on affected gene product that is oncogenic; what can these mutations do because they cause a gain of function?

tumor suppressor genes -loss of only a single tumor suppressor gene allele (haploinsufficiency) reduces activity of encoded protein enough to release brakes on cell proliferation and survival

mutations that affect ___ generally cause a loss of function and both alleles must be damaged before transformation can occur thus mutations in these usually behave in recessive fashion-exceptions?

driver mutations cancer requires initiated cell acquire a number of additional driver mutations, each of which contributes to development of cancer

mutations that contribute to development of malignant phenotype; first statrs a cell on path to malignancy is initiating mutations which is typically maintained in all of the cells of subsequent cancer. Because no single mutation appears to be fully transforming, how does cancer develop? takes time to develop, even in clincally aggressive cancers

growth factors NO-more commonly, signals transduced by other oncoproteins cause overexpression and increased secretion of growth factors, thereby initiating and amplifying autocrine loop

normal cells require stimulation by ___ to proliferate and most soluble ___ are made by one cell type and act on a neighboring cell to stimulate proliferation; some cancer cells acquire ability to synthesize the same ___ to which they are responsive, creating an autocrine loop (all same for blank); in tumors in which an autocrine loop is an important pathogenic element, is the gene for this affected?

intrinsic apoptotic pathway (abnormaltities in both though)

of intrinisic and extrinsic pathways to apoptosis, which is most frequently disabled in cancer?

inducing transient cell cycle arrest, senescence, or apoptosis p53's ability to act as a transcription factor 1. those that cause cell cycle arrest 2. those that cause apoptosis 3. those that enhance catabolic metabolism or inhibit anabolic metabolism

once activated, how does p53 twart neoplastic transformation? what do these effects stem from? what 3 categories do target genes that execute function of p53 fall into?

Darwinian evolution tumor progression mutator phenotype

once established, tumors evolve genetically during their outgrowth and progression under pressure of ___; undergo many cell divisions and more fit malignant ones come to dominate over time only to be replaced by more malignant subtypes over time; this tendency of tumors to become more aggressive over time is referred to as? as a result, even though malignant tumors are clonal in origin, by the time they become clinically evident their constituent cells are often extremely heterogenous genetically, paticularly tumors with?

transient cell cycle arrest (late in G1 phase, p53 dependent transcription of CDKN1A gene, maintaining RB in active state, pausing cell cycle) p53 induced senescence (permanent cell cycle arrest) p53 induced apoptosis (ultimate protective mechanism against neoplastic transformation; p53 directs transcription of several pro-apoptotic genes that tip balance in favor of cell death via intrinsic pathways

once p53 accumulates in a cell to levels that are sufficient to activate transcription of target genes, several different outcomes are possible, each more serious than the last with respect to ultimate fate of affected cell:

cyclin dependent kinases CDK-cyclin

orchestrate progression of cells through cell cycle ; ___ complexes phosphorylate crucial target proteins that drive cells forward through the cell cycle

RAS; intrinsic GTPase activity that is accelerated by GTPase activating proteins (GAP) which bind to active RAS and augment its GTPase activity, thereby terminating signal transduction (so GAPS prevent uncontrolled RAS activity)

point mutations of ___family genes constitute most common type of abnormality involving proto-oncogenes in human tumors; member of family of membrane associated small G proteins that bind GTP and GDP; flip back and forth between an excited signal transmitting state (bound to GTP) and inactive (GDP); activation is transient because it has?

TGF-beta

potent inhibitor of proliferation in most normal epithelial, endothelial, and hematopoietic cells; regulates cellular processes by bindnig to receptor I and II; under normal cirucmstances, these signals turn on antiproliferative genes and turn off genes that drive cell growth

release of factors that promote proliferation removal of growth suppressors enhanced resistance to cell death inducing angiogenesis activating invasion and metastasis evading immune destruction

proposed cancer enabling effects of inflammatory cells and resident stromal cells include:

signaling pathways that drive proliferation self sufficiency in growth

proto-oncogenes have multiple roles but all participate at some level, in? thus they may encode growth factors, growth factor receptors, signal transducers, transcription factors, or cell cycle components; the corresponding oncogenes generally encode oncoproteins that aserve fucntions similar to their normal counterparts with the important difference that they are usually constitutively active. As a result of this constitutive activity, pro growth oncoproteins endow cells with?

ERBB1, ERBB2, gene rearrangements

receptor tyrosine kinases can be constitutively activated in tumors by multiple mechanisms: few of better characterized oncogenic mutations involving growth factor receptors

oncoproteins

resemble normal products of proto-oncogenes but bear mutations that inactivate internal regulatory elements; consequently their activity in cells does not depend on external signals. Cells expressing these are freed from normal checkpoints and controls that limit growth and proliferate excessively

carcinogenesis 1. initiating mutation (normal cell heading to initiated precursors with stem cell like properties by carcinogen induced mutation) 2. acquisition of genomic instability (initiated precursor with stem cell like properties to precursor with mutator phenotype by mutation affecting genomic integrity) 3. acquisition of cancer hallmarks (precursor with mutator phenotype to founding cancer cells by additional driver mutations) 4. further genetic evolution (founding cancer cells to genetically heterogenous cancer by additional mutations, emergence of subciones) *accumulation of driver and passenger mutations growing over time

results from accumulation of complementary mutations in stepwise fashion over time; what is this stepwise fashion?

changes in tumor behavior following therapy i.e. one of most selective pressures cancers face is chemo and tumor that recur after therapy are almost always found to be resistant if same treatment is given again because therapy selects for preexistent subclones that have a genotype that allows them to survive

selection of fittest cells can explain history of cancer and?

WNT

signals through family of cell surface receptors called FRZ and stimulates several pathways, the central one involving beta-catenin and APC; in absence of this signaling, APC causes degradation of beta catenin, preventing its accumulation in the cytoplasm

anatomic location and vascular drainage of primary tumor and tropism of particular tumors for specific tissues

site at which circulating tumor cells leave capillaries to form secondary deposits is related to?

P13K/AKT signaling, receptor TK activity, MYC

some important points of crosstalk between progrowth signaling factors and cellular metabolism include:

autophagy

state of severe nutrient deficiency in which cells not only arrest their growth but also cannibalize their own organelles, proteins, and membranes as carbon sources for energy production

1. binding of growth factor to specific receptor 2. transient and limited activation of growth factor receptor which then activates several cytoplasmic signal transducing proteins 3. transmission of transduced signal to nucleus via cytoplasmic effector proteins and second messengers or by a cascade of signal transduction molecules 4. induction and activation of nuclear regulatory factors that initiate DNA transcription 5. expression of factors that promote entry and progression of cell into cell cycle, ultimately resulting in cell division 6. changes in expression of other genes that support cell survival and metabolic alterations that are needed for optimal growth happening in parallel

steps for normal cell response to growth factors

1. dissociation of cancer cells from one another (due to alterations in IC adhesion molecules) 2. degradation of basement membrane and interstitial connective tissue 3. involves changes in attachment of tumor cells to ECM proteins 4. locomotion, propelling tumor cells through degraded basement membranes and zones of matrix proteolysis

steps of invasion (first step of metastasis)

metastasis signature

subset of breast cancers has a metastatic gene expression signature similar to that found in metastases, although no clinical evidence for metastasis is apparent. Hypothesized that in these tumors with ___ most if not all cells develop a predilection for metastatic spread during early stage of carcinogenesis

clonal evolution model

suggests that as mutations accumulate in genetically unstable cancer cells and tumor become heterogenous, a rare subset of tumor cell subclones acquires a pattern of gene expression that is permissive for all steps involved in metastasis

the growth inhibitory activities of RB

transforming proteins of several oncogenic animal and human DNA viruses also act in part by neutralizing?

oncogene addiction

tumor cells are highly dependent on activity of one or more oncogenes; demonstrated by BCR ABL inhibitors

TP53

tumor suppressor gene that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis is most frequently mutated gene in human cancers; loss of function mutations in this are found in more than 50% of cancers and mutations of this occur in virtually every type of cancer, including carcinomas of lung, colon, and breast; most often mutations in both allels and are acquired in somatic cells (not germline)

inappropriate and continuous stimulation of nuclear transcription factors that drive growth promoting genes

ultimate consequence of deregulated mitogenic signaling pathways? so growth autonomy may also occur as a consequence of mutations affecting transcription factors that regulate expression of pro growth genes and cyclins

acts as proteins that put the break on cell cycle progression prevent cellular transformation through altering cell metabolism or by ensuring genomic stability

ways tumor suppressor genes functions so that more inclusive definition is: a protein or gene that is associated with suppression of any of various hallmarks of cancer

loss of function mutations that maintain genomic integrity passenger mutations

what appears to be a common early step on the road to malignancy, particularly in solid tumors? these that lead to genomic instability not only increase likelihood of acquiring driver mutations, but also greatly increase frequency of mutations that have no phenotypic consequence, so called ___, which are much more common than driver mutations. As a result, by the time a cell acquires all of the driver mutations that are needed for malignant behavior, it may bear hundreds or even thousands of acquired mutations

cancers arise from cells with stem cell like properties, cancer stem cells, that have capacity for self renewal and long term persistence

what does persistance of initiated cells during a long preclinical time suggest about cancer?

DNA damage goes unrepaired, driver mutations accumulate in oncogenes and other cancer genes, and cell marches blindly along a dangerous path leading to malignant transformation

what happens with loss of p53 function?

nonlethal genetic damage; any acquired mutation caused by exogenous agents such as virus or environmental chemicals or by endogenous products of cellular metabolism

what is at the heart of carcinogenesis? The initial damage or mutation may be caused by environmental exposures, inherited in germline, or may be spontaneous and random; term environmental in this context refers to?

p53 has a higher affinity for promoters and enhancers of DNA repair genes than for pro apoptotic genes thus the DNA repair pathway is stimulated first as p53 begins to accumulate; if p53 is sustained at this level due to ineffective DNA repair or other chronic stresses, epigenetic silencing of genes that are needed for cell cycle progression occurs, leading to senescence, alternatively, if enough p53 accumulates to stimulate transcription of pro apoptotic genes, the cell dies

what of 3 options does p53 do for cell first and why?

RAS mutations

when ___ are present in a tumor, activating mutations in a receptor TK are almost always absent, at least within dominant tumor clone, implying that in such tumors activated RAS can completely substitute for TK activity (i.e. lung adenocarcinomas fall into this)

vagaries of RAS structure and mode of signaling

why are strategies designed to target RAS difficult to inhibit with drugs?

aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for synthesis of cellular components, whereas mitochondrial oxidative phosphorylation does not; cell must duplicate all of its cellular components before it can divide and produce 2 daughter cells

why is it advantageous for cancer cells to rely on seeminly ineffecient glycolysis instead of oxidative phosphorylation?

targets genes like D cyclins upregulates expression of rRNA genes and processing upregulates program of gene expression that leads to metabolic reprogramming and Warburg effect (glycolytic enzymes, etc) master transcriptional regulator of cell growth

MYC activates expression of many genes that are involved in cell growth: ___ based on these effects, MYC can be considered? fastest growing human tumors are those with high levels of MYC

telomerase and can act together to reprogram somatic cells into pluripotent stem cells

MYC can upregulate expression of ___ and is one of a handful of transcription factors that can?

immortal and have limitless replicative potential evasion of senescence, evasion of mitotic crisis, and capacity for self renewal

all cancers contain cells that are ___ due to?

G1/S, G2/M G1/S

there are 2 main cell cycle checkpoints at the ___ transitions, each of which is tightly regulated by a balance of growth promoting and growth suppressing factors as well as by sensors of DNA damage; if activated, DNA damage sensors transmit singals that arrest cell cycle progression and initiate apoptosis (if damage cannot be repaired); defects in ___ are more important in cancer because these lead to dysregulated growth as well as a mutator phenotype which enbales cancer development and progression

failure of growth inhibition

whereas oncogenes drive proliferation of cells, products of tumor suppressor genes apply brakes to cell proliferation and abnormalities in them leads to ___ another fundamental hallmark of carcinogenesis