Neoplasia

Neoplasia

"new growth" -transformed because they continue to repli- cate, apparently oblivious to the regulatory influences that control normal cells; autonomy, increase in size regardless of their growth environment -All neoplasms depend on the host for their nutrition and blood supply; neoplasms derived from hormone responsive tissues often also require endocrine support -neoplasm often referred to as a "tumor" : benign and malignant

Basic components of tumors

(1) the parenchyma, made up of transformed or neoplastic cells, and (2) the supporting, host-derived, non-neoplastic stroma, made up of connective tissue, blood vessels, and host-derived inflammatory cells.

Carcinogenesis

-Beyond tumor initiation from a single founding cell, it is important to recognize that cancers continue to undergo Darwinian selection and therefore continue to evolve -cancers generally become more aggressive and acquire greater malignant potential, a phenomenon referred to as tumor progression -As a result of continuing mutation and Darwinian selec- tion, even though malignant tumors are monoclonal in origin they are typically genetically heterogeneous by the time of their clinical presentation. -eity may be enormous. Genetic evolution shaped by darwinian selection can explain the two most pernicious properties of cancers: the tendency over time for cancers to become both more aggressive and less responsive to therapy.

gene rearrangements

-Gene rearrangements may be produced by chromosomal translocations or inversions. Specific chromosomal trans- locations and inversions are highly associated with certain malignancies, particularly neoplasms derived from hematopoietic cells and other kinds of mesenchymal cells. -Some gene rearrangements result in overexpression of proto-oncogenes by removing them from their normal regulatory elements and placing them under control of an inappropriate, highly active promoter or enhancer. -Other oncogenic gene rearrangements create fusion genes encoding novel chimeric proteins. -Lymphoid tumors are most commonly associated with recurrent gene rearrangements. This relationship exists because normal lymphocytes express special enzymes that purposefully introduce DNA breaks during the processes of immunoglobulin or T cell receptor gene recombination. Repair of these DNA breaks is error-prone, and the result- ing mistakes sometimes result in gene rearrangements that activate proto-oncogenes. -Unlike lymphoid neoplasms, the cause of the DNA breaks that lead to gene rearrangements in myeloid neoplasms and sarcomas is unknown. -dentification of pathogenic gene rearrangements in car- cinomas has lagged because karyotypically evident trans- locations and inversions (which point to the location of important oncogenes) are rare in carcinomas

Important points of cross-talk between pro-growth signaling factors and cellular metabolism

-Growth factor receptor signaling. In addition to transmit- ting growth signals to the nucleus, signals from growth factor receptors also influence metabolism by upregulating glucose uptake and inhibiting the activity of pyruvate kinase, which catalyzes the last step in the glycolytic pathway, the conversion of phosphoenolpyr- uvate to pyruvate. -RAS signaling. Signals downstream of RAS upregulate the activity of glucose transporters and multiple glyco- lytic enzymes, thus increasing glycolysis; promote shunting of mitochondrial intermediates to pathways leading to lipid biosynthesis; and stimulate factors that are required for protein synthesis. -MYC. As mentioned earlier, pro-growth pathways upregulate expression of the transcription factor MYC, which drives changes in gene expression that support anabolic metabolism and cell growth BUT: tumor suppressors often inhibit metabolic pathways that support growth.

Deletions

-another prevalent abnormality in tumor cells. Deletion of specific regions of chromosomes may result in the loss of particular tumor suppressor genes. -Tumor suppressors generally require inactivation of both alleles in order for them to contribute to carcinogenesis.

Effective immune responses to Tumor Antigens

-It appears likely that immune reactions to cancers are initi- ated by the death of individual cancer cells, which occurs at some frequency in all cancers due to dysregulated growth, metabolic stresses, and hypoxia due to insufficient blood supply. -When tumor cells die they release "danger signals" (damage associated molecular patterns, see Chapter 5) that stimulate innate immune cells, including resident phagocytes and antigen presenting cells. -The dis- played tumor antigens are recognized by antigen-specific CD8+ T cells, which become activated, proliferate, differ- entiate into active CTLs, and home to the site of the tumor, where they recognize and kill tumor cells presenting neo- antigens in the context of their own MHC class I molecules -other cell types such as natural killer cells also have been implicated in anti-tumor responses, the quality and strength of CTL responses are believed to be of preeminent importance.

Evasion of Immune Surveillance

-Long one of the "holy grails" of oncology, the promise of therapies that enable the host immune system to recog- nize and destroy cancer cells is finally coming to fruition, largely due to a clearer understanding of the mechanisms by which cancer cells evade the host response. The specific factors that govern the outcome of interac- tions between tumor cells and the host immune system are numerous and are still being defined. In the face of this complexity, it is helpful to consider a few overarching principles: Cancer cells express a variety of antigens that stimulate the host immune system, which appears to have an important role in preventing the emergence of cancers. Despite the antigenicity of cancer cells, the immune response to established tumors is ineffective, and in some instances may actually promote cancer growth, due to acquired changes that allow cancer cells to evade anti-tumor responses and foster pro-tumor responses. Defining mechanisms of immune evasion and "immuno- manipulation" by cancer cells has led to effective new immunotherapies that work by reactivating latent host immune responses.

Malignant tumors

-Malignant neoplasms arising in "solid" mesenchymal tissues or its derivatives are called sarcomas, whereas those arising from the mesenchymal cells of the blood are called leukemias or lymphomas. -Sarcomas are des- ignated based on their cell-type composition -malignant neoplasms of epithelial cells are called carcinomas regardless of the tissue of origin. -Carcinomas that grow in a glandular pattern are called adenocarcinomas,and those that produce squamous cells are called squa- mous cell carcinomas; can have poorly differentiated or undifferentiated carcinomas

Four major functional classes of cancer genes

-Oncogenes are genes that induce a transformed pheno- type when expressed in cells by promoting increased cell growth. -Tumor suppressor genes are genes that normally prevent uncontrolled growth and, when mutated or lost from a cell, allow the transformed phenotype to develop. -Genes that regulate apoptosis primarily act by enhancing cell survival, rather than stimulating proliferation per se. -To this list may now be added genes that regulate interac- tions between tumor cells and host cells, as these genes are also recurrently mutated or functionally altered in certain cancers.

Morphologic features of anaplastic cells

-Pleomorphism (i.e., variation in size and shape) -Nuclear abnormalities, consisting of extreme hyperchro- matism (dark-staining), variation in nuclear size and shape, or unusually prominent single or multiple nucle- oli. -Tumor giant cells may be formed. -Atypical mitoses, which may be numerous. -Loss of polarity, such that anaplastic cells lack recogniz- able patterns of orientation to one another.

Gene Amplification

-Proto-oncogenes may be converted to oncogenes by gene amplification, with consequent overexpression and hyperactivity of otherwise normal proteins. - may produce several hundred copies of the gene, a change in copy number that can be readily detected by molecular hybridization with appropriate DNA probes. -

RB

-RB, a key negative regulator of the cell cycle, is directly or indirectly inactivated in most human cancers. -retinoblastoma gene (RB) was the first tumor suppressor gene to be discovered and is now considered the prototype of this family of cancer genes To account for the sporadic and familial occurrence of an identical tumor, Knudson, in 1974, proposed his now famous two-hit hypothesis, which in molecular terms can be stated as follows: Two mutations (hits) are required to produce retinoblas- toma. These involve the RB gene, which has been mapped to chromosomal locus 13q14. Both of the normal alleles of the RB locus must be inactivated (hence the two hits) for the development of retinoblastoma (Fig. 6.19). In familial cases, children inherit one defective copy of the RB gene in the germ line; the other copy is normal. Retinoblastoma develops when the normal RB gene is lost in retinoblasts as a result of somatic mutation. Because in retinoblastoma families a single germ line mutation is sufficient to transmit disease risk, the trait has an autosomal dominant inheritance pattern. • In sporadic cases, both normal RB alleles are lost by somatic mutation in one of the retinoblasts. The end result is the same: a retinal cell that has lost both of the normal copies of the RB gene becomes cancerous. -now evident that biallelic loss of this gene is a fairly common feature of several tumors, including breast cancer, small cell cancer of the lung, and bladder cancer. -The function of the RB protein is to regulate the G1/S checkpoint, the portal through which cells must pass before DNA replication commences. -The RB gene product, RB, is a DNA-binding protein that serves as a point of integration for these diverse signals, which ultimately act by altering the phosphoryla- tion state of RB.

ABL

-Several non-receptor tyrosine kinases function as signal transduction molecules. In this group, ABL is the best defined with respect to carcinogenesis. -tyrosine kinase activity that is dampened by internal negative regulatory domains. -The crucial role of BCR-ABL in cancer has been con- firmed by the dramatic clinical response of patients with chronic myeloid leukemia to BCR-ABL kinase inhibitors. -BCR-ABL also is an example of the concept of oncogene addiction, wherein a tumor is profoundly dependent on a single signaling molecule.

Insensitivity to growth-inhibitory signals

-Whereas oncogenes encode proteins that promote cell growth, the products of tumor suppressor genes apply brakes to cell proliferation. -Disruption of such genes renders cells refractory to growth inhibition and mimics the growth-promoting effects of oncogenes. -In principle, anti-growth signals can prevent cell prolif- eration by several complementary mechanisms. The signal may cause dividing cells to enter G0 (quiescence), where they remain until external cues prod their reentry into the proliferative pool. Alternatively, the cells may enter a post- mitotic, differentiated pool and lose replicative potential. Nonreplicative senescence, alluded to earlier, is another mechanism of escape from sustained cell growth. And, as a last-ditch effort, the cells may be programmed for death by apoptosis. As we will see, tumor suppressor genes have all these "tricks" in their toolbox designed to halt wayward cells from becoming malignant.

Self-sufficiency in Growth Signals

-The self-sufficiency in growth that characterizes cancer cells generally stems from gain-of-function mutations that convert proto-oncogenes to oncogenes. -Oncogenes encode proteins called oncoproteins that promote cell growth, even in the absence of normal growth-promoting signals. cell proliferation can be readily resolved into the following steps: 1. Binding of a growth factor to its specific receptor on the cell membrane 2. Transient and limited activation of the growth factor receptor, which in turn activates several signal- transducing proteins on the inner leaflet of the plasma membrane 3. Transmissionofthetransducedsignalacrossthecytosol to the nucleus by second messengers or a cascade of signal transduction molecules 4. Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription and the biosynthesis of other cellular components that are needed for cell division, such as organelles, membrane components, and ribosomes 5. Entry and progression of the cell into the cell cycle, resulting ultimately in cell division note: is that the increased production of oncoproteins does not by itself lead to sustained prolif- eration of cancer cells. There are two built-in mechanisms, cell senescence and apoptosis, that oppose oncogene- mediated cell growth.

Evasion of cell death

-Tumor cells frequently contain mutations in genes that regulate apoptosis, making the cells resistant to cell death. -evasion of apop- tosis by cancer cells occurs mainly by way of acquired mutations and changes in gene expression that disable key components of the intrinsic pathway, or that reset the balance of regulatory factors so as to favor cell survival in the face of intrinsic stresses

Limitless replicative potential

-Tumor cells, unlike normal cells, are capable of limitless replication. As discussed previously in the context of cel- lular aging (Chapter 2), most normal human cells have a capacity of at most 70 doublings. Thereafter, the cells lose the ability to divide and enter replicative senescence. This phenomenon has been ascribed to progressive shortening of telomeres at the ends of chromosomes. -Markedly eroded telomeres are recognized by the DNA repair machinery as double-stranded DNA breaks, leading to cell cycle arrest and senescence, mediated by TP53 andRB. In cells in which TP53 or RB mutations are disabled by mutations, the nonhomologous end-joining pathway is activated in a last-ditch effort to save the cell, joining the shortened ends of two chromosomes-> inappropriate repair system results in dicentric chromosomes pulled apart at anaphase, causing new DSBs- genomic instability -follows that for tumors to acquire the ability to grow indefinitely, loss of growth restraints is not enough; both cellular senescence and mitotic catastrophe must also be avoided

Cancer

-a genetic disorder caused by DNA muta- tions -Genetic alterations in cancer cells are heritable, being passed to daughter cells upon cell division. As a result, cells harboring these alterations are subject to Dar- winian selection (survival of the fittest, arguably the most important scientific concept in biology). -mutations with a growth or survival advantage outcompete their neighbors and thus dominate the population; at time of tumor initiation, selective advantages are conferred to a single cell- all tumors are clonal- but, select for aggressive sub clones with time ("progression") -Mutations and epigenetic alterations impart to cancer cells a set of properties that are referred to collectively as cancer hallmarks.

Aneuploidy

-defined as a number of chromosomes that is not a multiple of the haploid state; for humans, that is a chromosome number that is not a multiple of 23. -remarkably common in cancers -Aneuploidy frequently results from errors of the mitotic checkpoint -Mechanistic data establishing aneuploidy as a cause of carcinogenesis, rather than a consequence, have been dif- ficult to generate. -but, statistical analysis suggests aneuploidy tends to increase the copy number of key oncogenes and decrease the copy number of potent tumor suppressors

Cancer Genes

-disease caused by mutations that alter the function of of a finite subset of the 20,000 or so human genes -Causative mutations that give rise to cancer genes may be acquired by the action of environmental agents, such as chemicals, radiation, or viruses, may occur spon- taneously, or may be inherited in the germ line.

Interactions between enviro and genetic factors

-evidence suggests that sporadic cancers can largely be attributed to environmental factors or acquired predisposing conditions, lack of family history does not preclude an inherited component. -genetic factors may alter the risk for developing environ- mentally induced cancers

Cyclins and Cycllin dependent kinases

-growth factors transduce signals that stimulate the orderly progression of cells through the various phases of the cell cycle, the process by which cells replicate their DNA in preparation for cell divi- sion. You will recall that progression of cells through the cell cycle is orchestrated by cyclin-dependent kinases (CDKs), which are activated by binding to cyclins, so called because of the cyclic nature of their production and degradation. -CDK-cyclin complexes phosphorylate crucial target proteins that drive cells forward through the cell cycle. -While cyclins arouse the CDKs, CDK inhibitors (CDKIs), of which there are many, silence the CDKs and exert negative control over the cell cycle. Expression of these inhibitors is downregulated by mitogenic signaling pathways, thus promoting the progression of the cell cycle. -There are two main cell cycle checkpoints, one at the G1/S transition and the other at the G2/M transition, each of which is tightly regulated by a balance of growth- promoting and growth-suppressing factors, as well as by sensors of DNA damage (Chapter 1). If activated, these DNA-damage sensors transmit signals that arrest cell cycle progression and, if cell damage cannot be repaired, initiate apoptosis. Once cells pass through the G1/S checkpoint, they are committed to undergo cell division. For unclear reasons, par- ticular lesions vary widely in frequency across tumor types, but they fall into two major categories. 1)Gain-of-function mutations involving CDK4 or D cyclins. 2)Loss-of-function mutations involving CDKIs.

Age and cancer

-in general, the frequency of cancer increases with age. Most cancer deaths occur between 55 and 75 years of age; the rate declines, along with the population base, after 75 years of age. -accumulation of somatic mutations -also is responsible for slightly more than 10% of all deaths among children younger than 15 years of age

MicroRNAs and cancer

-microRNAs (miRNAs) are non- coding, single-stranded RNAs, approximately 22 nucle- otides in length, that function as negative regulators of genes. They inhibit gene expression posttranscriptionally by repressing translation or, in some cases, by messenger RNA (mRNA) cleavage. -accumulating evidence indicates that miRNAs also can contribute to carcinogenesis. Specifi- cally, if the target of a miRNA is a tumor suppressor gene, then overactivity of the miRNA can reduce the tumor sup- pressor protein. - For example, downregulation or deletion of certain miRNAs in some leu- kemias and lymphomas results in increased expression ofBCL2, an anti-apoptotic gene. Thus, by negatively regulat- ing BCL2, such miRNAs behave as tumor suppressor genes.

Transforming growth factor B pathway

-much is known about the circuitry that applies brakes to the cell cycle, the molecules that transmit anti- proliferative signals to cells are less well characterized. -In many forms of cancer, the growth-inhibiting effects of the TGF-β pathways are impaired by mutations affect- ing TGF-β signaling. -Thus, TGF-β can function to prevent or promote tumor growth, depending on the state of other genes in the cell.

Metastasis

-tumor cells grow they randomly accumulate mutations, creating subclones with distinct combinations of mutations. One possibility is that only rare tumor cells accumulate all of the mutations necessary for metastasis, and that this accounts for the inefficiency of the process. alternative idea is that some tumors acquire all of the mutations needed for metastasis early in their development, and that these are the tumors that are fated to be "bad actors.": metastasis an intrinsic property of the tumor, develops during early carcinogenesis -whether there are genes whose principal or sole contribution is to control programs of gene expression that promote metastasis.

cancer incidence

14.1 mill new cancer cases worldwide in 2012, leading to 8.2 mill deaths -death rate has decreased by roughly 10% in women and 20% in men since 1995- decreased use of tobacco, increase in early detection

Summary: Invasion and Metastasis

Ability to invade tissues, a hallmark of malignancy, occurs in four steps: loosening of cell-cell contacts, degradation of ECM, attachment to novel ECM components, and migration of tumor cells. • Cell-cell contacts are lost by the inactivation of E-cadherin through a variety of pathways. • Basement membrane and interstitial matrix degradation is mediated by proteolytic enzymes secreted by tumor cells and stromal cells, such as MMPs and cathepsins. • Proteolytic enzymes also release growth factors sequestered in the ECM and generate chemotactic and angiogenic frag- ments from cleavage of ECM glycoproteins. • The metastatic site of many tumors can be predicted by the location of the primary tumor. Many tumors arrest in the first capillary bed they encounter (lung and liver, most commonly). • Some tumors show organ tropism, probably due to activation of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site.

Acquired predisposing conditions

Acquired conditions that predispose to cancer include disorders associated with chronic inflammation, immu- nodeficiency states, and precursor lesions.

Oncometabolism

Another surprising group of genetic alterations discovered through tumor genome sequencing studies are mutations in enzymes that participate in the Krebs cycle. Of these, mutations in isocitrate dehydrogenase (IDH) have gar- nered the most interest, as they have revealed a new mech- anism of oncogenesis termed oncometabolism -The proposed steps in the oncogenic pathway involving IDH are as follows:• IDH acquires a mutation that leads to a specific amino acid substitution involving residues in the active site of the enzyme. As a result, the mutated protein loses it ability to function as an isocitrate dehydrogenase and instead acquires a new enzymatic activity that catalyzes the production of 2-hydroxglutarate (2-HG). • 2-HG in turn acts as an inhibitor of several other enzymes that are members of the TET family, including TET2.• TET2 is one of several factors that regulate DNA meth- ylation, which you will recall is an epigenetic modifica- tion that controls normal gene expression and often goes awry in cancer. According to the model, loss of TET2 activity leads to abnormal patterns of DNA methylation. • Abnormal DNA methylation in turn leads to misexpres- sion of currently unknown cancer genes, which drive cellular transformation and oncogenesis. -according to this scenario, mutated IDH acts as an oncoprotein by producing 2-HG, which is considered a prototypical oncometabolite.

Vascular Dissemination and Homing of TumroCells

Because of their invasive properties, tumor cells fre- quently escape their sites of origin and enter the circu- lation. It is now recognized from studies of "liquid biopsies," blood samples taken from patients with solid tumors, that millions of tumor cells are shed daily from even small cancers -Given the ease with which tumor cells access the circula- tion, it is apparent that the ability of cancers cells to leave the circulation, invade, and grow to clinically significant sizes at other sites in the body is (fortunately for the patient) highly inefficient. -Several factors seem to limit the metastatic potential of circulating tumor cells. ---host immune responses in circulation ---hard to adhere to normal vascular beds Despite these limiting factors, if neglected, virtually all malignant tumors will eventually produce macroscopic metastases. The site at which metastases appear is related to two factors: the anatomic location and vascular drain- age of the primary tumor, and the tropism of particular tumors for specific tissues. Tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ. • Chemokines may have an important role in determining the target tissues for metastasis. For instance, many cancers express the chemokine receptor CXCR4, which has been implicated in the extravasation of circulating tumor cells originating from tumors such as breast cancer. • In some cases, the target tissue may be a nonpermissive environment, "unfavorable soil," so to speak, for the growth of tumor seedlings. For example, although they are well vascularized, skeletal muscle and spleen are rarely sites of metastasis.

Benign and Malignant tumors summary

Benign and malignant tumors can be distinguished from one another based on the degree of differentiation, rate of growth, local invasiveness, and distant spread. Benign tumors resemble the tissue of origin and are well dif- ferentiated; malignant tumors are poorly or completely undif- ferentiated (anaplastic). Benign tumors tend to be slow growing, whereas malignant tumors generally grow faster. Benign tumors are well circumscribed and have a capsule; malignant tumors are poorly circumscribed and invade the surrounding normal tissues. Benign tumors remain localized to the site of origin, whereas malignant tumors are locally invasive and metastasize to distant sites.

passenger mutations

By contrast, passenger mutations are acquired mutations that are neutral in terms of fitness and do not affect cellu- lar behavior; they just come along for the proverbial ride. Because they occur at random, passenger mutations are sprinkled throughout the genome, whereas driver muta- tions tend to be tightly clustered within cancer genes -A second, more nefarious effect of passenger mutations is that they create genetic variants that, while initially neutral, may provide tumor cells with a selective advantage in the setting of therapy.

Downstream Signal-Transducing Proteins

Cancer cells often acquire growth autonomy as a result of mutations in genes that encode components of signaling pathways downstream of growth factor receptors. -The signaling proteins that couple growth factor receptors to their nuclear targets are activated by ligand binding to growth factor receptors.

Growth Factors

Cancers may secrete their own growth factors or induce stromal cells to produce growth factors in the tumor microenvironment -Normally, cells that produce the growth factor do not express the cognate receptor, preventing the formation of positive feedback loops within the same cell. -Some cancer cells acquire growth self-sufficiency by acquiring the ability to synthesize the same growth factors to which they are responsive. -Another mechanism by which cancer cells acquire growth self-sufficiency is by interaction with stroma.

Differentiation and Anaplasia

Differentiation refers to the extent to which neoplasms resemble their parenchymal cells of origin, both morpho- logically and functionally; lack of differentiation is called anaplasia. -Tumors composed of undifferentiated cells are said to be anaplastic ("backward formation"), a feature that is a reliable indicator of malignancy. -at least some cancers arise from stem cells in tissues; in these tumors, failure of dif- ferentiation of transformed stem cells, rather than dedif- ferentiation of specialized cells, accounts for their anaplastic appearance. -Well-differentiated tumor cells are likely to retain the functional capabilities of their normal counterparts, whereas anaplastic tumor cells are much less likely to have specialized functional activities.

Driver

Driver mutations are mutations that alter the function of cancer genes and thereby directly contribute to the devel- opment or progression of a given cancer.

Enviro factors

Environmental exposures appear to be the dominant risk factors for many common cancers, suggesting that a high fraction of cancers are potentially preventable. -Diet: obesity Smoking -Alcohol consumption -Reproductive history- estrogen stimulation, particularly that unopposed by progesterone-- alter in breast and endometrium -Infectious agents

Evasion of apoptosis summary

Evasion of cell death by cancers mainly involves acquired abnormalities that interfere with the intrinsic (mitochondrial) pathway of apoptosis. • The most common abnormalities involve loss of p53 function, either by way of TP53mutations or overexpression of the p53 inhibitor MDM2. • Other cancers evade cell death by overexpressing anti-apop- totic members of the BCL2 family, such as BCL2, BCL-XL, and MCL1, which protect cells from the action of BAX and BAK, the pro-apoptotic members of the BCL2 family. • In a large majority of follicular B-cell lymphomas, BCL2 levels are high because of a (14;18) translocation that fuses the BCL2gene with regulatory elements of the immunoglobulin heavy chain gene. • Inhibitors of MDM2 (which activate p53) and inhibitors of BCL2 family members induce the death of cancer cells by stimulating the intrinsic pathway of apoptosis and are being developed as therapeutic agents.

Sustained angiogenesis

Even if a solid tumor possesses all of the genetic aberra- tions that are required for malignant transformation, it cannot enlarge beyond 1 to 2 mm in diameter unless it has the capacity to induce angiogenesis. -tumors require delivery of oxygen and nutrients and removal of waste products; presumably the 1- to 2-mm zone represents the maximal distance across which oxygen, nutrients, and waste can diffuse to and from blood vessels. -By permit- ting tumor cells access to these abnormal vessels, angio- genesis also contributes to metastasis. Angiogenesis is thus an essential facet of malignancy. -How do growing tumors develop a blood supply? The current paradigm is that angiogenesis is controlled by a balance between angiogenesis promoters and inhibitors; in angiogenic tumors this balance is skewed in favor of promoters.

Altered Cellular Metabolism

Even in the presence of ample oxygen, cancer cells dem- onstrate a distinctive form of cellular metabolism charac- terized by high levels of glucose uptake and increased conversion of glucose to lactose (fermentation) via the glycolytic pathway -This phenomenon, called the Warburg effect and also known as aerobic glycolysis, has been recog- nized for many years -Clinically, the "glucose-hunger" of tumors is used to visualize tumors via positron emission tomography (PET) scanning, in which patients are injected with 18F-fluorodeoxyglucose, a glucose derivative that is preferentially taken up into tumor cells (as well as normal, actively dividing tissues such as the bone marrow). Most tumors are PET-positive, and rapidly growing ones are markedly so. QUESTION: why is it advantageous for a cancer cell to rely on seem- ingly inefficient glycolysis (which generates two molecules of ATP per molecule of glucose) instead of oxidative phos- phorylation (which generates up to 36 molecules of ATP per molecule of glucose)? ANSWER: Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components, whereas mitochondrial oxidative phosphor- ylation does not. -growing cell has a strict biosynthetic requirement; it must duplicate all of its cellular components—DNA, RNA, proteins, lipid, and organelles—before it can divide and produce two daughter cells. While oxidative phosphoryla- tion yields abundant ATP, it fails to produce any carbon moieties that can be used to build the cellular components needed for growth (proteins, lipids, and nucleic acids). -in actively growing cells only a small frac- tion of the cellular glucose is shunted through the oxidative phosphorylation pathway, such that on average each mol- ecule of glucose metabolized produces approximately four molecules of ATP. -So how is this profound reprogramming of metabolism, the Warburg effect, triggered in growing normal and malignant cells? As might be guessed, metabolic repro- gramming is produced by signaling cascades downstream of growth factor receptors, the very same pathways that are deregulated by mutations in oncogenes and tumors suppressor genes in cancers. -in cancer cells this reprogram- ming persists due to the action of oncogenes and the loss of tumor suppressor gene function.

fibroadenoma

Fibroadenoma of the female breast is another common mixed tumor. This benign tumor contains a mixture of proliferating ductal elements (adenoma) embedded in loose fibrous tissue (fibroma). Unlike pleomorphic adenoma, only the fibrous component is neoplastic, but the term fibroadenoma remains in common usage.

Crucial role of RB in the cell cycle

Hallmarks of Cancer one of the four key regulators of the cell cycle (p16, cyclin D, CDK4, RB) is mutated in most human cancers.The initiation of DNA replication (S phase) requires the activity of cyclin E/CDK2 complexes, and expression of cyclin E is dependent on the E2F family of transcription factors. Early in G1, RB is in its hypophosphorylated active form, and it binds to and inhibits the E2F family of transcription factors, preventing transcription of cyclin E. Hypophosphorylated RB blocks E2F-mediated transcription in at least two ways (Fig. 6.20). First, it sequesters E2F, preventing it from interacting with other transcriptional activators. Second, RB recruits chromatin remodeling proteins, such as histone deacet- ylases and histone methyltransferases, which bind to the promoters of E2F-responsive genes such as cyclin E. These enzymes modify chromatin at the promoters to make DNA insensitive to transcription factors. This situation is changed on mitogenic signaling. Growth factor signaling leads to cyclin D expression and activation of cyclin D-CDK4/6 complexes. The level of cyclin D-CDK4/6 activity is tempered by antag- onists such as p16, which is itself subject to regulation by growth inhibitors such as TGFβ that serve to set a threshold for mitogenic responses. If the stimulus is suf- ficently strong, cyclin D-CDK4/6 complexes phosphor- ylate RB, inactivating the protein and releasing E2F to induce target genes such as cyclin E. Cyclin E/CDK complexes then stimulate DNA replication and progres- sion through the cell cycle. When the cells enter S phase, they are committed to divide without additional growth factor stimulation. During the ensuing M phase, the phosphate groups are removed from RB by cellular phosphatases, regenerating the hypophosphorylated form of RB. E2F is not the sole target of RB. The versatile RB protein binds to a variety of other transcription factors that regulate cell differentiation. For example, RB stimulates myocyte-, adipocyte-, melanocyte-, and macrophage- specific transcription factors. Thus, the RB pathway couples control of cell cycle progression at G1 with dif- ferentiation, which may explain how differentiation is associated with exit from the cell cycle. -It is now accepted that loss of normal cell cycle control is central to malignant transformation and that at least one of the four key regulators of the cell cycle (p16, cyclin D, CDK4, RB) is mutated in most human cancers

Invasion of Extracellular matrix

Human tissues are organized into a series of compartments separated from each other by two types of ECM: basement membranes and interstitial connective tissue (Chapter 1). Although organized differently, each type of ECM is com- posed of collagens, glycoproteins, and proteoglycans. -Tumor cells must interact with the ECM at several stages in the metastatic cascade (see Fig. 6.27). A carcinoma first must breach the underlying basement membrane, then tra- verse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular base- ment membrane. Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several sequential steps 1)loosening of intercellular connections between tumor cells. 2) Local degradation of the basement membrane and interstitial connective tissue. 3) Changes in attachment of tumor cells to ECM proteins. 4) Locomotion

Immortality summary

In normal cells, which lack expression of telomerase, the short- ened telomeres generated by cell division eventually activate cell cycle checkpoints, leading to senescence and placing a limit on the number of divisions a cell may undergo. In cells that have disabled checkpoints, DNA repair pathways are inappropriately activated by shortened telomeres, leading to massive chromosomal instability and mitotic crisis. Tumor cells reactivate telomerase, thus staving off mitotic catastrophe and achieving immortality.

Invasion and metastasis

Invasion, and metastasis, the major causes of cancer- related morbidity and mortality, result from complex interactions involving cancer cells, stromal cells, and the extracellular matrix (ECM). These interactions can be broken down into a series of steps consisting of local inva- sion, intravasation into blood and lymph vessels, transit through the vasculature, extravasation from the vessels, formation of micrometastases, and growth of micrometas- tases into macroscopic tumors (Fig. 6.27). Predictably, this sequence of steps may be interrupted at any stage by either host-related or tumor-related factors. For the purpose of discussion, the metastatic cascade can be subdivided into two phases: (1) invasion of ECM and (2) vascular dissemi- nation and homing of tumor cells.

RB summary

Like other tumor suppressor genes, both copies of RBmust be dysfunctional for tumor development to occur. In cases of familial retinoblastoma, one defective copy of theRBgene is present in the germ line, so that only one additional somatic mutation is needed to completely eliminate RB function. RB exerts anti-proliferative effects by controlling the G1-to-S transition of the cell cycle. In its active form, RB is hypophos- phorylated and binds to E2F transcription factors. This interac- tion prevents transcription of genes like cyclin E that are needed for DNA replication, and so the cells are arrested in G1. Growth factor signaling leads to cyclin D expression, activation of cyclin D-CDK4/6 complexes, inactivation of RB by phos- phorylation, and thus release of E2F. Loss of cell cycle control is fundamental to malignant transfor- mation. Almost all cancers have a disabled G1checkpoint due to mutation of either RBor genes that affect RB function, such as cyclin D, CDK4, and CDKIs. Many oncogenic DNA viruses, like HPV, encode proteins (e.g., E7) that bind RB and render it nonfunctional.

Pleomorphic adenoma

MC benign tumor of salivary glands

Malignant tumors

Malignant, as applied to a neoplasm, implies that the lesion can invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death: CANCERS

Genetic Lesions in Cancer summary

Mutations in cancer cells fall into two major classes, driver (pathogenic) mutations and passenger (neutral) mutations. Passenger mutations may become driver mutations if selective pressure on the tumor changes, for example, in the setting of treatment with an effective therapeutic drug. Tumor cells may acquire driver mutations through several means, including point mutations and nonrandom chromo- somal abnormalities that contribute to malignancy; these include gene rearrangements, deletions, and amplifications. Gene rearrangements (usually caused by translocations, but sometimes by inversions of other more complex events) con- tribute to carcinogenesis by overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity. Deletions frequently affect tumor suppressor genes, whereas gene amplification increases the expression of oncogenes. Overexpression of miRNAs can contribute to carcinogenesis by reducing the expression of tumor suppressors, while dele- tion or loss of expression of miRNAs can lead to overexpres- sion of proto-oncogenes. Tumor suppressor genes and DNA repair genes also may be silenced by epigenetic changes, which involve reversible, heri- table changes in gene expression that occur not by mutation but by methylation of the promoter.

point muts

Point mutations that convert proto-oncogenes into oncogenes generally produce a gain- of-function by altering amino acid residues in a domain that normally holds the protein's activity in check.

Self-sufficiency in growth signals summary

Proto-oncogenes:normal cellular genes whose products promote cell proliferation • Oncogenes:mutant or overexpressed versions of proto- oncogenes that function autonomously without a requirement for normal growth-promoting signals Oncoproteins promote uncontrolled cell proliferation by several mechanisms: Stimulus-independent expression of growth factor and its receptor, setting up an autocrine loop of cell proliferation (e.g., PDGF-PDGF receptor in brain tumors) Mutations in genes encoding growth factor receptors or tyrosine kinases leading to constitutive signaling Amplification of EGF receptor family genes such as HER2in breast cancer Fusion of portions of the ABLtyrosine kinase gene and the BCRprotein gene, creating a BCR-ABLfusion gene encoding a constitutively active tyrosine kinase, in certain leukemias Mutations in genes encoding signaling molecules RAS commonly is mutated in human cancers and normally flips between resting GDP-bound state and active GTP- bound state; mutations block hydrolysis of GTP to GDP, leading to unchecked signaling Overproduction or unregulated activity of transcription factors Translocation of MYC in some lymphomas leads to overex- pression and unregulated expression of its target genes con- trolling cell cycling and survival Mutations that activate cyclin genes or inactivate negative regulators of cyclins and cyclin-dependent kinases Complexes of cyclins with CDKs drive the cell cycle by phos- phorylating various substrates and normally are controlled by CDK inhibitors. Mutations in genes encoding cyclins, CDKs, and CDK inhibitors result in uncontrolled cell cycle progres- sion and are found in a wide variety of cancers including mela- nomas and brain, lung, and pancreatic cancers.

Factors influencing local balance of angiogenic and anti-angiogenic factors

Relative lack of oxygen due to hypoxia stabilizes HIF1α, an oxygen-sensitive transcription factor mentioned earlier, which then activates the transcription of proan- giogenic cytokines such as VEGF. These factors create an angiogenic gradient that stimulates the proliferation of endothelial cells and guides the growth of new vessels toward the tumor. Mutations involving tumor suppressors and oncogenes in cancers also tilt the balance in favor of angiogenesis. For example, p53 stimulates expression of anti- angiogenic molecules, such as thrombospondin-1, and represses expression of proangiogenic molecules, such as VEGF. Thus, loss of p53 in tumor cells provides a more permissive environment for angiogenesis. The transcription of VEGF also is influenced by signals from the RAS-MAP kinase pathway, and gain-of- function mutations in RAS or MYC upregulate the pro- duction of VEGF. Notably, elevated levels of VEGF can be detected in the serum and urine of a significant fraction of cancer patients.

Immune Evasion by Cancers

Since the immune system is capable of recognizing and eliminating nascent cancers, it follows that tumors that reach clinically significant sizes must be composed of cells that are either invisible to the host immune system or that express factors that actively suppress host immunity. -These include acquired muta- tions in β2-microglobulin that prevent the assembly of functional MHC class I molecules, and increased expres- sion of a variety of proteins that inhibit CTL function. These proteins work by activating what is referred to asimmune checkpoints, inhibitory pathways that normally are crucial for maintaining self-tolerance and controlling the size and duration of immune responses so as to minimize collateral tissue damage. -One of the best-characterized immune checkpoints involves a protein called PD-L1 (programmed cell death ligand 1), which is often expressed on the surface of tumor cells (Figure 6.30). When PD-L1 engages its receptor, PD-1, on CTLs, the CTLs become unresponsive and lose their ability to kill tumor cells. -The discovery of checkpoints that shut off anti-tumor immunity has led to the development of antibodies that block these checkpoints and release the brakes on the immune response. -remarkable response of advanced cancers to immune checkpoint inhibitors has energized other work focused on harnessing the immune system to combat cancer. -Beyond complications of immunotherapy, it also should be recognized that the host immune response to tumors is not an unalloyed blessing. -To summarize, while the future appears very bright for cancer immunotherapy, important hurdles remain to be cleared. At present, response and resistance to immune checkpoint inhibitors are unpredictable, and new biomark- ers are needed to better tailor therapies for individual patients.

Most common lesions

Squamous metaplasia and dysplasia of bronchial mucosa,seen in in habitual smokers—a risk factor for lung car- cinoma (Chapter 13) • Endometrial hyperplasia and dysplasia, seen in women with unopposed estrogenic stimulation—a risk factor for endometrial carcinoma (Chapter 19) • Leukoplakia of the oral cavity, vulva, and penis, which may progress to squamous cell carcinoma (Chapters 15, 18, and 19) • Villous adenoma of the colon, associated with a high risk for progression to colorectal carcinoma (Chapter 15)

TGF-B, Contact inhibition and APC_B Catenin pathways summary

TGF-βinhibits proliferation of many cell types by activation of growth-inhibiting genes such as CDKIsand suppression of growth-promoting genes such as MYCand those encoding cyclins. TGF-βfunction is compromised in many tumors by mutations in its receptors (colon, stomach, endometrium) or by muta- tional inactivation of SMADgenes that transduce TGF-βsignal- ing (pancreas). E-cadherin maintains contact inhibition, which is lost in malig- nant cells. The APCgene exerts anti-proliferative actions by regulating the destruction of the cytoplasmic protein β-catenin. With a loss of APC, β-catenin is not destroyed, and it translocates to the nucleus, where it acts as a growth-promoting transcription factor. In familial adenomatous polyposis syndrome, inheritance of a germ line mutation in the APCgene and sporadic loss of the sole normal allele causes the development of hundreds of colonic polyps at a young age. Inevitably, one or more of these polyps evolves into a colonic cancer. Somatic loss of both alleles of the APCgene is seen in approximately 70% of spo- radic colon cancers.

TP53 summary

TP53encodes p53, the central monitor of stress in the cell, which can be activated by anoxia, inappropriate oncogene signaling, or DNA damage. Activated p53 controls the expres- sion and activity of genes involved in cell cycle arrest, DNA repair, cellular senescence, and apoptosis. • DNA damage leads to activation of p53 by phosphorylation. Activated p53 drives transcription of CDKN1A (p21), which prevents RB phosphorylation, thereby causing a G1-S block in the cell cycle. This pause allows the cells to repair DNA damage. If DNA damage cannot be repaired, p53 induces cellular senes- cence or apoptosis. Of human tumors, 70% demonstrate biallelic mutations in TP53. Patients with the rare Li-Fraumeni syndrome inherit one defective copy of TP53in the germ line, such that only one additional mutation is required to lose normal p53 function. Li-Fraumeni syndrome patients are prone to develop a wide variety of tumors. As with RB, p53 can be incapacitated when bound by proteins encoded by oncogenic DNA viruses such as HPV.

Genetic Lesions in cancer

The genetic changes found in cancers vary from point mutations involving single nucleotides to abnormalities large enough to produce gross changes in chromosome structure. -Driver and passenger mutations

Local Invasion

The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of surrounding tissues, whereas most benign tumors grow as cohesive expansile masses that remain localized to their sites of origin -benign tumors usually develop a ring of compressed fibrous tissue- activates and compresses, making easy to remove surgically; but, not all benign neoplasms are encapsulated -Next to the development of metastases, invasiveness is the feature that most reliably distinguishes cancers from benign tumors: cancers lack well defined capsules- invasive mode of growth

Epidemiology of Cancer summary

The incidence of cancer varies with age, geographic factors, and genetic background. The geographic variation in cancer incidence results mostly from different environmental expo- sures. Cancer can occur at any age, but is most common in older adults. Environmental factors implicated in carcinogenesis include infectious agents, smoking, alcohol, diet, obesity, reproductive history, and exposure to carcinogens. Cancer risk rises in certain tissues in the setting of increased cellular proliferation caused by chronic inflammation or hor- monal stimulation. Epithelial cell linings may develop morphologic changes that signify an increased risk for developing cancer; such lesions are referred to as precursor lesions. The risk for developing cancer is modified by interactions between environmental exposures and genetic variants.

TP53 - Guardian of the Genome

The p53-encoding tumor suppressor gene, TP53, is the most commonly mutated gene in human cancer. -a transcription factor that thwarts neoplastic transformation by three interlocking mechanisms: activa- tion of temporary cell cycle arrest (termed quiescence), induction of permanent cell cycle arrest (termed senes- cence), or triggering of programmed cell death (termedapoptosis). If RB is a "sensor" of external signals, p53 can be viewed as a central monitor of internal stress, directing the stressed cells toward one of these pathways. Three mechanisms by which genes suppress neoplastic transformation 1)p53-mediated cell cycle arrest may be considered the primor- dial response to DNA damage 2)p53-induced senescence is a form of permanent cell cycle arrest 3) p53-induced apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against neoplastic trans- formation. To summarize, p53 is activated by stresses such as DNA damage and assists in DNA repair by causing G1arrest and inducing the expression of DNA repair genes. -Confirming the importance of TP53 in controlling car- cinogenesis, more than 70% of human cancers have a defect in this gene, and the remaining malignant neo- plasms often have defects in genes upstream or down- stream of TP53.

Evasion of Immune Surveillance summary

Tumor cells can be recognized by the immune system as non- self and destroyed. Antitumor activity is mediated by predominantly cell-mediated mechanisms. Tumor antigens are presented on the cell surface by MHC class I molecules and are recognized by CD8+CTLs. The different classes of tumor antigens include products of mutated genes, overexpressed or aberrantly expressed pro- teins, and tumor antigens produced by oncogenic viruses. Immunosuppressed patients have an increased risk for devel- opment of cancer, particularly types caused by oncogenic DNA viruses. In immunocompetent patients, tumors may avoid the immune system by several mechanisms, including selective outgrowth of antigen-negative variants, loss or reduced expression of histocompatibility molecules, and immunosuppression medi- ated by expression of certain factors (e.g., TGF-β, PD-1 ligands) by the tumor cells. Antibodies that overcome some of these mechanisms of immune evasion are now approved for treatment of patients with advanced forms of cancer.

Sustained angiogenesis summary

Vascularization of tumors is essential for their growth and is controlled by the balance between angiogenic and anti- angiogenic factors that are produced by tumor and stromal cells. Hypoxia triggers angiogenesis through the actions of HIF-1αon the transcription of the proangiogenic factor VEGF. Many other factors regulate angiogenesis; for example, p53 induces synthesis of the angiogenesis inhibitor thombospondin-1, while RAS, MYC, and MAPK signaling all upregulate VEGF expression and stimulate angiogenesis. VEGF inhibitors are used to treat a number of advanced cancers and prolong the clinical course, but are not curative.

Altered cell. metabolism summary

Warburg metabolism is a form of pro-growth metabolism favoring glycolysis over oxidative phosphorylation. It is induced in normal cells by exposure to growth factors and becomes fixed in cancer cells due to the action of certain driver mutations. Many oncoproteins (RAS, MYC, mutated growth factor recep- tors) induce or contribute to Warburg metabolism, and many tumor suppressors (PTEN, NF1, p53) oppose it. Stress may induce cells to consume their components in a process called autophagy. Cancer cells may accumulate muta- tions to avoid autophagy, or may corrupt the process to provide nutrients for continued growth and survival. Some oncoproteins such as mutated IDH act by causing the formation of high levels of "oncometabolites" that alter the epigenome, thereby leading to changes in gene expression that are oncogenic.

Contact inhibition

When cancer cells are grown in the laboratory, their proliferation fails to be inhibited when they come in contact with each other. -in sharp contrast to nontransformed cells, which stop proliferating once they form confluent monolayers. -Cell-cell contacts in many tissues are mediated by homodimeric interactions between transmembrane pro- teins called cadherins. -One mechanism is mediated by the tumor suppressor gene NF2. Its product, neurofibromin-2, more com- monly called merlin, acts downstream of E-cadherin in a signling pathway that helps fo maintain contact inhibi- tion. -A second mechanism by which E-cadherin may regu- late contact inhibition involves its ability to bindβ-catenin, another signaling protein.

adenoma

a benign tumor that arises in or resembles glandular tissue; can lack a glandular growth pattern

Hallmarks of cancer

all cancers display eight fundamental changes in cell physi- ology, which are considered the hallmarks of cancer.These changes are illustrated in Fig. 6.17 and consist of the following: • 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 -The acquisition of the genetic and epigenetic alterations that confer these hallmarks may be accelerated by cancer- promoting inflammation and by genomic instability.

Tyrosinase

an enzyme involved in melanin biosynthesis that is expressed only in normal melanocytes and melanomas. It may be surprising that the immune system is able to respond to this normal self-antigen. The probable explanation is that tyrosinase is normally produced in such small amounts and in so few normal cells that it is not recognized by the immune system and fails to induce tolerance.

Papillomas

benign epithelial neoplasms growing on any surface that produce microscopic or macroscopic fingerlike fronds

benign tumor

benign when its microscopic and gross characteristics are considered to be rela- tively innocent, implying that it will remain localized and is amenable to local surgical removal. -generally designated by adding the suffix -oma to the cell type from which the tumor arises

Tumor Antigens

cancers, due to their inherent genetic instability, also accumulate passenger mutations. These may be particularly abundant in cancers that are caused by mutagenic exposures (e.g., sunlight, smoking). All of these varied mutations may generate new protein sequences (neoantigens) that the immune system has not seen and therefore is not tolerant of and can react to. In some instances, unmutated proteins expressed by tumor cells also can stimulate the host immune response. ex: tyrosinase ex: cancer-testis antigens

APC

clue to the importance of E-cadherin are hereditary disease adenomatous polyposis coli (APC). This disorder is characterized by the development of numer- ous adenomatous polyps in the colon that have a very high incidence of transformation into colonic cancers. The polyps consistently show loss of a tumor suppressor gene called APC (named for the disease), which exerts anti-proliferative effects in an unusual manner -encodes a cytoplasmic protein whose dominant func- tion is to promote the degradation of β-catenin, which has several functions. -APC behaves as a typical tumor suppressor gene. Indi- viduals born with one mutated allele typically are found to have hundreds to thousands of adenomatous polyps in the colon by their teens or twenties; these polyps show loss of the other APC allele.

Metastasis

defined by the spread of a tumor to sites that are physically discontinuous with the primary tumor and unequivocally marks a tumor as malignant, as by definition benign neoplasms do not metastasize. -In general, the more anaplastic and the larger the primary neoplasm, the more likely is metastatic spread, but as with most rules there are exceptions. -Extremely small cancers have been known to metastasize; conversely, some large and ominous-looking lesions may not.

Malignant neoplasms

disseminate by one of three pathways: (1) seeding within body cavities (occurs when neoplasms invade a natural body cavity), (2) lymphatic spread (more typical of carcinomas, whereas hematogenous spread is favored by sarcomas; A "sentinel lymph node" is the first regional lymph node that receives lymph flow from a primary tumor- biopsy of sentinel lymph node allows determination of the extent of spread of the condition), or (3) hematogenous spread (the favored pathway for sarcomas, carcinomas use it as well)

Epigenetic modifications and cancer

epigenetics refers to reversible, heritable changes in gene expression that occur without mutation -changes involve post translational modifications of histones and DNA methylation, both of which affect gene expression. -n normal, differentiated cells, the major portion of the genome is not expressed- cancer cells are characterized by a global DNA hypomethylation and selective promoter-specific hypermethylation -it has become evident during the past several years that tumor suppressor genes are sometimes silenced by hypermethylation of promoter sequences, rather than by mutation. In addition, genome-wide hypomethylation has been shown to cause chromosomal instability and can induce tumors in mice. -The epigenetic state of particular cell types—a feature described as the epigenetic context—also dictates their response to signals that control growth and differentiation.

growth factor receptors

ext group in the sequence of signal transduction is growth factor receptors. Some growth factor receptors have an intrinsic tyrosine kinase activity that is activated by growth factor binding, while others signal by stimulat- ing the activity of downstream proteins. Many of the myriad growth factor receptors function as oncoproteins when they are mutated or if they overexpressed -These tumors are exquisitely sensitive to the mitogenic effects of small amounts of growth factors. -In each of these cases, the mutated recep- tors are constitutively active, delivering mitogenic signals to cells even in the absence of growth factors.

cancer-testis antigens

group of tumor antigens encoded by genes that are silent in all adult tissues except germ cells in the testis—hence their name. Although the protein is present in the testis it is not expressed on the cell surface in a form that can be rec- ognized by CD8+ T cells, because sperm do not express MHC class I molecules. Thus, for all practical purposes these antigens are tumor specific and are therefore capable of stimulating anti-tumor immune responses.

carcinoma in situ

hen dysplastic changes are severe and involve the entire thickness of the epithelium, the lesion is referred to as carcinoma in situ, a preinvasive stage of cancer

Autophagy

is a state of severe nutrient deficiency in which cells not only arrest their growth, but also canni- balize their own organelles, proteins, and membranes as carbon sources for energy production -If this adaptation fails, the cells die. Tumor cells often seem to be able to grow under marginal environmental conditions without triggering autophagy, suggesting that the path- ways that induce autophagy are deranged -several genes that promote autophagy are tumor sup- pressors -some advantages: under condi- tions of severe nutrient deprivation, tumor cells may use autophagy to become "dormant," a state of metabolic hibernation that allows cells to survive hard times for long periods.

precursor lesions

localized disturbances of epithelial differentiation that are associated with an elevated risk for developing carcinoma. They may arise secondary to chronic inflammation or hormonal disturbances (in endocrine-sensitive tissues), or may occur spontaneously.

polyp

mass that projects above a mucosal surface

Dysplastic Epithelium

recognized by a loss in the uniformity of individual cells and in their architectural orientation. -dysplastic cells exhibit considerable pleomor- phism and often possess abnormally large, hyperchromatic nuclei. -dysplasia not synonymous with cancer, but is often noted next to malignant neoplasms

Teratoma

special type of mixed tumor that contains recognizable mature or immature cells or tissues derived from more than one germ cell layer, and sometimes all three.

RAS

the most commonly mutated oncogene in human tumors. -Normally, RAS flips back and forth between an excited signal- transmitting state and a quiescent state. -inactive when bound to GDP -Activated RAS stimulates downstream regulators of prolif- eration by several interconnected pathways that converge on the nucleus and alter the expression of genes that regulate growth, such as MYC. -RAS most commonly is activated by point mutations in amino acid residues that are either within the GTP- binding pocket or in the enzymatic region that carries out GTP hydrolysis-- interfere with the breakdown of GTP, which is essential to inactivate RAS

medical terminology exceptions

the terms lymphoma, mesothelioma, melanoma, and seminoma are used for malignant neoplasms. Unfortunately for students, these exceptions are firmly entrenched in medical terminology. -Hamartoma is a mass of disorganized tissue indigenous to the particular site, such as the lung or the liver. While traditionally considered developmental malfor- mations, many hamartomas have clonal chromosomal aberrations that are acquired through somatic muta- tions and on this basis are now considered to be neoplastic. -Choristoma is a congenital anomaly consisting of a het- erotopic nest of cells. For example, a small nodule of well-developed and normally organized pancreatic tissue may be found in the submucosa of the stomach, duodenum, or small intestine. The designation -oma,connoting a neoplasm, imparts to these lesions an undeserved gravity, as they are usually of trivial significance.

Distinguishing benign and malignant neoplasms

three fundamental features by which most benign and malignant tumors can be distinguished: dif- ferentiation and anaplasia, local invasion, and metasta- sis. In general, rapid growth also signifies malignancy, but many malignant tumors grow slowly and as a result growth rate is not a reliable discriminator between good and bad actors.

Nuclear Transcription Factors

ultimate consequence of signaling through oncopro- teins such as RAS or ABL is inappropriate and continu- ous stimulation of nuclear transcription factors that drive the expression of growth-promoting genes. -Dysregulation of MYC promotes tumorigenesis by simultaneously promoting the progression of cells through the cell cycle and enhancing alterations in metab- olism that support cell growth. -Genes acti- vated by MYC include several growth-promoting genes, including cyclin-dependent kinases (CDKs), whose prod- ucts drive cells into the cell cycle (discussed next), and genes that control pathways that produce the building blocks (e.g., amino acids, lipids, nucleotides) that are needed for cell growth and division.