Robbins and Cotran Ch 7- Neoplasia

How can you make immortal human epithelial cells

(1) activation of RAS; (2) inactivation of RB; (3) inactivation of p53; (4) inactivation of PP2A, a tumor suppressive phosphatase that is a negative regulator of many signaling pathways; and (5) constitutive expression of telomerase. Cells bearing all of these alterations are immortal and produce invasive, fully malignant growths when injected into immunodeficient mice.

What are the three interrelated factors that are critical for immortality of cancer cells

(1) evasion of senescence- upregulation of p53 and INK4a/p16 and disruption of RB-dependent G1/S cell cycle checkpoint (2) evasion of mitotic crisis (dysfunctional p53 that doesnt sense exposed chromosome ends from lack of telomeres (can join naked ends of two chromosomes ->new ds-DNA breaks ->repeated bridge-fusion-breakge cycles -> mitotic catastrophe -> death) or (cells have telomerase so they can survive longer, Telomere maintenance is seen in virtually all types of cancers) (3) the capacity for self-renewal.

What are two mutually exclusive patterns of gene amplification seen

(1) multiple small extrachromosomal structures called double minutes and (2) homogeneous staining regions. The latter derive from the insertion of the amplified genes into new chromosomal locations, which may be distant from the normal location of the involved oncogene. The affected chromosomal regions lack a normal pattern of light- and dark-staining bands, appearing homogeneous in karyotypes

What are the two pathways that lead to apoptosis

(1) the extrinsic (death receptor) pathway, triggered by death receptors of the tumor necrosis factor (TNF) receptor family, such as FAS, and their ligands; and (2) the intrinsic (mitochondrial) pathway, initiated by various stresses, such as the absence of growth factors and DNA damage. The intrinsic pathway appears to be the primary arbitrator of life and death in cancer cells, as cancer cells are subject to a number of intrinsic stresses that can initiate apoptosis The most important mechanisms involve loss of p53 function, either through mutation or through antagonism by MDM2, and reduced egress of cytochrome c from mitochondria as a result of upregulation of anti-apoptotic factors that stabilize the mitochondrial membrane such as BCL2, BCL-XL, and MCL-1. Less commonly, tumors suppress apoptosis by unregulating members of the inhibitor of apoptosis (IAP) family. Activation of this pathway leads to permeabilization of the mitochondrial outer membrane and release of molecules, such as cytochrome c, that initiate apoptosis. BH3-only proteins (BIM, BAD, BID, PUMA) neutralize anti-apoptotic BCL2 and BCL-XL, so they promote apoptosis leaked cytochrome c binds to APAF-1 and activates caspase-9, whcih in turn cleaves and activates the executioner caspases Inhibitor of apoptosis proteins (IAPs) block action of caspase-9

What are some things that help cancer cells survive in circulation

-Clumping together and attachment to platelets to enhance survival -Tumor cells may also express anionic substances such as polyphosphate that activate factor XII (contact factor), resulting in fibrin deposition and further stabilization of tumor emboli, which may enhance the ability of the cells to arrest en masse within capillary beds.

Helicobacter pylori facts

-H. pylori infection is implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas. -it involves increased epithelial cell proliferation in a background of chronic inflammation. As in viral hepatitis, the inflammatory milieu contains numerous genotoxic agents, such as reactive oxygen species -H. pylori contains cytotoxin-associated A (CagA) gene. Although H. pylori is noninvasive, CagA penetrates into gastric epithelial cells, where it has a variety of effects including the initiation of a signaling cascade that mimics unregulated growth factor stimulation -see development of B cell gastric lymphoma, polymorphisms in the promoters of inflammatory cytokines such as IL-1β and TNF. It is thought that H. pylori infection leads to the appearance of H. pylori -reactive T cells, which in turn stimulate a polyclonal B-cell proliferation.

How does RB work "Governor of Proliferation"

-Key negative regulator in G1/S and is consequently directly or indirectly inactivated in most human cancers -Exists in an active hypophosphorylated state in quiescent cells and an inactive hyperphosphorylated state in cells passing through the G 1 /S cell cycle transition -How to compromise function: Mutating both alleles (loss of function) or a shift from active to inactive state (hyperphosphorylated) caused by gain of function that upregulates CDK/cyclin D or loss of function mutation that change CDK inhibitors

Important Epstein-Barr virus facts

-Linked to Burkitt lymphoma. Causes B cell lymphomas and nasopharyngeal carcinomas -EBV binds so CD21 to infect B cells likely in tonsils after salivary exposure -Latent membrane protein 1 (LMP-1) activates NF-kB and JAK/STAT signaling pathway to promote B cell survival and proliferation. It also prevents apoptosis by activating BCL2. -EBV also has an IL-10 homologue to suppress T cell activation by macrophages, and EBNA-2 to mimic active Notch receptor and activate cyclin D and SRC family of proto-oncogenes -EBV proteins can be highly immunogenic for CTLs -Burkitt lymphoma cells do not express LMP-1, EBNA2, and other EBV proteins that drive B-cell growth and immortalization. -In regions where Burkitt lymphoma is endemic, concomitant infections such as malaria impair immune competence, allowing sustained B-cell proliferation. Eventually, T-cell immunity directed against EBV antigens such as EBNA2 and LMP-1 eliminates most of the EBV-infected B cells, but a small number of cells downregulate expression of these immunogenic antigens. These cells persist indefinitely, even in the face of normal immunity. Lymphomas from this almost all have dysregulated MYC -In contrast to Burkitt lymphoma, tumors in immunosuppressed patients usually express LMP-1 and EBNA2, which are antigenic and would normally be recognized by cytotoxic T cells. Also, in contrast to Burkitt lymphoma, B-cell tumors in immunosuppressed individuals usually lack MYC translocations. -Nasopharyngeal carcinomas express LMP-1 and have prominent T cell infiltrate and express PD-L1

Explain the relevance of the the proto-oncogene transcription factor MYC

-MYC is the master transcriptional regulator of cell growth -immediate early response gene induced by RAS/MAPK -MYC acitvates many genes involved in cell growth including D cyclins (involved in cell cycle progression), upregulation of rRNA (enhances assembly of ribosomes), upregulates genes related to metabolic reprogramming and Warburg effect (upregulates multiple glycolytic enzymes and factors involved in glutamine metabolism -Upregulates expression of telomerase -One of several transcription factors that act together to reprogram somatic cells into pluripotent stem cells -MYC is frequently deregulated in cancer by genetic alteration of the gene itself, amplification, or insertion of enhancer elements/stabilization of MYC

Human T-cell leukemia virus type 1 (HTLV-1)

-Only human retrovirus firmly impllicated in pathogenesis of cancer in humans -Causes adult T-cell leukemia/lymphoma. Has tropism for CD4+ T cells -Transfer requires sex, blood, or breastfeeding -Site of integration of virus is identical within all cells of a given cancer -The HTLV-1 genome contains the gag, pol, env, and long-terminal-repeat regions typical of all retroviruses, but, in contrast to other leukemia viruses, it contains two other genes referred to as tax (essential for viral replication becasuse it stimulates viral RNA transcription) and HBZ (HBZ is a transcription factor, and Tax and HBZ alter the transcription of host cell genes and interact with certain host cell signaling proteins)

What is the benefit of cancer enabling inflammation

-Release of factors that promote inflammation (EGF, proteases liberate growth factors from ECM) -Removal of growth suppressors (proteases from inflammatory cells degrade adhesion molecules) -Enhanced resistance to cell death -Induced angiogenesis (VEGF) -Activiating invasion and metastasis (proteases from macrophages remodel ECM and TNF/EGF stimulate tumor cell motility and TGF-B promote epithelial to mesenchymal transition) -Evasion of immune desstruction (cancer can contain M2 macrophages induced by IL-4 and IL-13; can produce TGF-B)

What are some ways that tumors can evade the immune system

-Selective outgrowth of antigen-negative varients (do not produce reactive neoantigen; high neoantigen burden makes tumors more likely to respond to checkpoint therapy) -Loss or reduced expression of MHC molecules (no MHC class 1 means no attack by CTLs, but they can still express ligands for NK cell activating receptors) -Engagement of pathways to inhibit T cell activation (promote expression of inhibitory CTLA4 on T cells, upregulate PDL1 and PDL2 to cause programmed cell death on effector T cells -Secretion of immunosuppressive factors (TGF-beta, IL-10, prostaglandin E2 ,tryptophan metabolites, and VEGF so T cells can't move from vascular bed to tumor) -Induction of T regs to be immunosuppressive The most common toxicities associated with checkpoint blockade are autoimmunity and/or inflammatory damage to organs .

Relevant facts about tumor antigens

-Tumor antigens (neoantigens) can be made from genes bearing passenger and driver mutations that can bind to MHC and induce a CTL response against the cell -Cells can overexpress or abarently express normal cell proteins, like tyrosinase in melanomas (melanin biosynthesis enzyme) -Cells can abarently express antigen, like MAGE (melanoma antigen gene) or cancer-testis antigens -Tumor antigens can be produced by oncogenic viruses and recognized by CTLs so virus-infected cells can be killed (like Epstein-Barr virus or HPV) these proteins are presented by MHC 1 molecules so CTLs can recognize them

Hepatitis B and C viruses important facts

-ne key molecular step may be activation of the NF-κB pathway, which blocks apoptosis, allowing the dividing hepatocytes to incur genotoxic stress and to accumulate mutations. Although this seems to be a dominant mechanism in the pathogenesis of virus-induced hepatocellular carcinoma, the HBV genome also contains genes that may directly promote the development of cancer. For example, an HBV gene known as HBx can activate a variety of transcription factors and several signal transduction pathways.

What is the role of tyrosine kinase receptors in cancer

-receptor tyrosine kinases are transmembrane proteins with an extracellular growth factor-binding domain and a cytoplasmic tyrosine kinase domain -. Normally the receptor is activated transiently by binding of a specific growth factor, an event that induces a rapid change in receptor conformation to an active dimeric state. The activated receptor then autophosphorylates tyrosine residues in its own intracellular tail, and these modified residues serve as sites for recruitment of other signaling molecules including RAS and PI3K, key players in receptor tyrosine kinase signaling -The oncogenic versions of these receptors are associated with mutations that lead to constitutive, growth factor-independent tyrosine kinase activity. Hence, the mutant receptors deliver mitogenic signals to the cell continuously, even in the absence of growth factor in the environment.

What is RB

A cell cycle checkpoing component. It's a tumor suppressive "pocket" protein theat binds E2F transcription factors in its hypophosphorylated state, preventing G1/S transition Defects in G1/S checkpoint are more important that G2/, because they lead to dysregulated growth and impair DNA repair -> mutator phenotype

How do mixed tumors form, like a mixed tumor of the salivary gland

A classic example is the mixed tumor of the salivary gland, which contains epithelial components scattered within a myxoid stroma that may contain islands of cartilage or bone ( Fig. 7.2 ). All of these elements arise from a single neoplastic clone capable of producing both epithelial and mesenchymal cells; thus the preferred designation of this neoplasm is pleomorphic adenoma. The great majority of neoplasms, including mixed tumors, are composed of cells from a single germ layer (mesoderm, endoderm, or ectoderm). An exception is a tumor called a teratoma, which contains recognizable mature or immature cells or tissues belonging to more than one germ cell layer (and sometimes all three). Teratoma originates from totipotential germ cells that are normally present in the ovary and testis and sometimes also found in abnormal midline embryonic rests hamartomas are disorganized masses composed of cells indigenous to the involved tissue; most have underlying clonal chromosome aberrations Choristoma is a misplaced rest of cells

What is the significance of EML4-ALK in cancer

ALK is a receptor tyrosine kinase that may be produced in a constitutively active form as a result of a gene rearrangement. For example, in a subset of lung adenocarcinomas, a deletion on chromosome 5 fuses part of the ALK gene with part of another gene called EML4 . The resulting EML4-ALK fusion gene encodes a chimeric EML4-ALK protein with constitutive tyrosine kinase activity.

Describe the PML-RARA gene in acute promyelocytic leukemia (APML)

APML is virtually always associated with a reciprocal translocation between chromosomes 15 and 17 that produces a PML-RARA fusion gene The PML-RARα oncoprotein has diminished affinity for retinoids, such that at physiologic levels retinoids do not bind to PML-RARα to any significant degree. In this "unliganded" state, it retains the capacity to bind DNA, but instead of activating transcription, it inhibits transcription through recruitment of transcriptional repressors. This interferes with the expression of genes that are needed for differentiation, leading to a "pile-up" of proliferating myeloid progenitors that replace normal bone marrow elements. When given in pharmacologic doses, all- trans retinoic acid (ATRA) binds to PML-RARα and causes a conformational change that results in the displacement of repressor complexes and the recruitment of different complexes that activate transcription. There also is evidence that ATRA-bound PML-RARA complexes are degraded more rapidly. These changes overcome the block in gene expression, causing the neoplastic myeloid progenitors to differentiate into neutrophils and die (this is called differentiation therapy)

Name two types of epigenetic aberrations that contribute to malignancy

Aberrant DNA methylation in cancer cells is responsible for the silencing of some tumor suppressor genes, while tumor-specific changes in histone modifications may have far-ranging effects on gene expression

How do tumor cells activate host antitumor immunity by checkpoint inhibitors

Activation of host antitumor immunity by checkpoint inhibitors. (A) Blockade of the CTLA4 surface molecule with an inhibitor antibody allows cytotoxic CD8+ T cells (CTLs) to engage B7 family coreceptors, leading to T-cell activation. (B) Blockade of PD-1 receptor or PD-1 ligand by inhibitory antibodies abrogates inhibitory signals transmitted by PD-1, again leading to activation of CTLs. Tumors may evade immune responses by losing expression of antigens or major histocompatibility complex (MHC) molecules or by producing immunosuppressive cytokines or ligands such as PD-L1 for inhibitory receptors on T cells.

How does p53 maintain the integrity of the genome

Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G 1 and induction of DNA repair by transcriptional upregulation of the cyclin-dependent kinase inhibitor CDKN1A (encoding the cyclin-dependent kinase inhibitor p21) and GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of the p53 gene, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.

What does APC do Gatekeeper of colonic neoplasia

Adenomatous polyposis coli. See germline mutations. Component of WNT signaling pathway (controls cell growth and differentiation). APCA keeps beta- catenin in check in signaling pathway. Cells that lose APC behave as if they are being continuously stimulated by WNT and show elevated expression of genes that are regulated by β-catenin (proto-oncogene)

Why do tumors become more aggressive over time

Although tumors start out as clonal, during the expansion process individual tumor cells acquire additional mutations at random, especially if a driver mutation confers a mutator phenotype. Consequently cells constituting tumors are often extremely heterogenous genetically and tumor subclones ocmpete for access to nutrients and microenvironmental niches

Where do cancer stem cells come from

At least some cells in all cancers must be stem cell-like; these cells are sometimes referred to as cancer stem cells. These 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.

What do the members of the CIP/KIP family do

Block the cell cycle by binding to cyclin-CDK complexes. p21 is induced by tumor suppressor p53. p27 responds to growth suppressors such as TGF-beta

What can solid tumors express to enhance lymph node spread

CD44 Of interest in this regard is the CD44 adhesion molecule, which is expressed on normal T lymphocytes and is used by these cells to migrate to selective sites in lymphoid tissues. Such migration is accomplished by the binding of CD44 to hyaluronate on high endothelial venules. Solid tumors also often express CD44, which appears to enhance their spread to lymph nodes and other metastatic sites.

Where would a loss of function mutation be that inhibits G1/S progression

CDK inhibitor (like p16(CDKN2A)) RB (tumor suppressor gene specific to G1/S) TP53 (tumor suppressor gene specific to G1/S)

what causes cancer cachexia

Cancer cachexia is a hypercatabolic state defined by a loss of muscle mass (with or without loss of fat) that cannot be explained by diminished food intake. The precise causes of cancer cachexia are not known, but inflammatory mediators, particularly TNF, IL-1, and IL-6, appear to have important roles. Specifically, it appears that cytokines increase the degradation of major skeletal muscle structural proteins, such as myosin heavy chain, through signaling pathways that lead to ubiquitination of target proteins followed by proteolysis via the proteasome.One factor that may contribute to fat loss is a protein called lipid mobilizing factor, which has been detected in the sera and urine of patients with advanced cancer and which appears to sensitize adipocytes to lipolytic stimuli.

How do antigen presenting cells help CTLs recognize cancer

Cancer cells necrose/apoptose -> dendritic cells/macrophages ingest tumor antigen and pesent in MHC 2 and cross-present in MHC 1 to naive CD8+ CTLs with costimulaltion by costimulatory molecules upregulated on APCs from DAMPS released from tumor cells -> tumor-specific CTLs migrate from lymph nodes to tumor and kill tumor cells

What do the most heavily mutated cancers have a defect in?

Cancers with DNA polymerase mutations are the most heavily mutated of all human cancers and, presumably because of a high burden of neoantigens, appear to have excellent responses to immune checkpoint inhibitors.

How can you measure residual leukemia cells in a CML

Detection of BCR-ABL transcripts by PCR gives a measure of the residual leukemia cells in treated patients with CML

How do tumor cells perform locomotion

Cells must attach to the matrix at their leading edge, detach from the matrix at their trailing edge, and contract the actin cytoskeleton to ratchet forward. Such movement seems to be stimulated and directed by several types of factors, which likely vary among different types of tumors. These include: • Tumor cell-derived cytokines including chemokines and growth factors (e.g., insulin-like growth factors), which act as autocrine motility factors • Cleavage products of matrix components (e.g., collagen, laminin) • Stromal cell-derived paracrine factors such as hepatocyte growth factor/scatter factor, which binds to the receptor tyrosine kinase MET on tumor cells and stimulates motility

What does VHL do

Component of protein complex that covalently links ubiquitin chains to specific protein substrates so they get degraded by proteasome. In the presence of oxygen, HIF1α is hydroxylated and binds to VHL, leading to its ubiquitination and degradation. In hypoxic environments the hydroxylation reaction does not occur, and HIF1α escapes recognition by VHL. Loss-of-function mutations in VHL prevent the ubiquitination and degradation of HIF1α, even under normoxic conditions, and are accordingly associated with increased levels of angiogenic growth factors and alterations in cellular metabolism that favor growth.

Where would a gain of function mutation be that affects the G1/S checkpoint

D cyclin genes (D1, D2, D3; all functionally interchangable) CDK4

What in B and T cells is prone to error

Developing B and T cells both express a pair of gene products, RAG1 and RAG2, that carry out V(D)J segment recombination, permitting the assembly of functional antigen receptor genes. In addition, after encountering antigen, mature B cells express a specialized enzyme called activation-induced cytosine deaminase (AID), which is required for both immunoglobulin gene class switch recombination and somatic hypermutation. These processes are associated with AID-induced DNA breaks or nucleotide substitutions, both of which are prone to errors such as translocations and mutations that cause lymphoid neoplasm

Name the three pathways that cancers used to spread

Direct seeding of body cavities or surfaces, lymphatic spread (most common initial dissemination of carcinomas), hematogenous spread (more typical of sarcomas but also seen with carcinomas)

Direct vs indirect-acting carcinogens

Direct-acting carcinogens do not require metabolic conversion to become carcinogenic. Indirect-acting carcinogens require metabolic conversion to become active carcinogens; the carcinogenic products are called ultimate carcinogens . Some of the most potent indirect chemical carcinogens—the polycyclic hydrocarbons—are present in fossil fuels. Others, for example, benzo[ a ]pyrene (the active component of soot, which Potts showed to be carcinogenic), are formed during the high-temperature combustion of tobacco in cigarettes and are implicated in the causation of lung cancer. Polycyclic hydrocarbons also are produced from animal fats during the process of broiling or grilling meats and are present in smoked meats and fish. The aromatic amines and azo dyes are another class of indirect-acting carcinogens that were widely used in the past in the aniline dye and rubber industries Most indirect carcinogens are metabolized by cytochrome P-450-dependent monooxygenases. Genes that encode these are polymorphic, so susceptibility to carcinogenesis is related to the particular polymorphic variants than an individual inherits (like people who have P450 gene CYP1A1 have a 7x higher risk of developing lung cancer from light smoking)

What is mutated in the HER2 mutation

ERBB2 encodes a different member of the receptor tyrosine kinase family, HER2. Rather than being activated by point mutations, the ERBB2 gene is amplified in certain breast carcinomas, leading to overexpression of the HER2 receptor and constitutive tyrosine kinase activity.

How does inflammation enhance cancer cell survival

Enhanced resistance to cell death. Recall that detachment of epithelial cells from basement membranes and from cell-cell interactions leads to a form of cell death called anoikis . It is suspected that tumor-associated macrophages prevent anoikis by expressing adhesion molecules such as integrins that promote direct physical interactions with the tumor cells. There is also substantial evidence that stromal cell-cancer cell interactions increase the resistance of cancer cells to chemotherapy, presumably by activating signaling pathways that promote cell survival in the face of stresses such as DNA damage.

Describe tumor dormancy and how tumors can make a metastatic site habitable

Even when metastatic cells take root and survive within distant tissues, they may fail to grow. This phenomenon, called tumor dormancy, is well described in melanoma and in breast and prostate cancer. Although the molecular mechanisms of productive colonization are still being unraveled, a consistent theme seems to be that tumor cells secrete cytokines, growth factors, and ECM molecules that act on the resident stromal cells, which in turn make the metastatic site habitable for the cancer cell. For example, breast cancer cells that are metastatic to bone often secrete parathyroid hormone-related protein (PTHRP), which stimulates osteoblasts to make RANK ligand (RANKL). RANKL then activates osteoclasts, which degrade the bone matrix and release growth factors embedded within it, like IGF and TGF-β. These in turn bind to receptors on the cancer cells, activating signaling pathways that support the growth and survival of the cancer cells.

What do CDK4+D cyclins do What is RB

Form a complex that phosphorylates RB, allowing the cell to progress through the G 1 restriction point RB-Tumor suppressive "pocket" protein that binds E2F transcription factors in its hypophosphorylated state, preventing G 1 /S transition. Interacts with transcription factors that regulate differentiation

How do growth inhibitors and growth factors relate to RB?

Growth inhibitors (like TGF-beta and P53) stimulate CDK inhibitors and p16(INK4a) which inactivate cyclins (like cyclin D/CDK4,6 and cyclin E/CDK2), leadindg to hypophosphorylated RB so E2F is bound and E2F+RB bind to E2F site and cause transcriptional block Growth factors (like EGF and PDGF) activate cyclins causing a hyperphosphorylated RB so E2F by itself is at E2F site and trascription is activated

Viral and bacterial oncogenesis key facts

HTLV-1: a retrovirus that is endemic in Japan, the Caribbean, and parts of South America and Africa that causes adult T-cell leukemia/lymphoma. • HTLV-1 encodes two viral proteins, Tax and HBX, which are suspected to contribute to leukemogenesis through uncertain mechansisms. • After a long latent period (decades), a small fraction of HTLV-1-infected individuals develop adult T-cell leukemia/lymphoma, a CD4+ tumor that arises from an HTLV-1-infected cell, presumably due to acquisition of additional mutations in the host cell genome. HPV: an important cause of benign warts, cervical cancer, and oropharyngeal cancer. • Oncogenic types of HPV encode the viral oncoproteins E6 and E7, which bind to p53 and Rb, respectively, with high affinity and neutralize their function. • Development of cancer is associated with integration of HPV into the host genome and additional mutations needed for acquisition of cancer hallmarks. • HPV cancers can be prevented by vaccination against high-risk HPV types. EBV: ubiquitous herpesvirus implicated in the pathogenesis of Burkitt lymphomas, B-cell lymphomas in patients with T-cell immunosuppression (HIV infection, transplant recipients), and several other cancers. • The EBV genome harbors several genes encoding proteins that trigger B-cell signaling pathways; in concert, these signals are potent inducers of B-cell growth and transformation. • In the absence of T-cell immunity, EBV-infected B cells can rapidly "grow out" as aggressive B-cell tumors. • In the presence of normal T-cell immunity, a small fraction of infected patients develop EBV-positive B-cell tumors (Burkitt lymphoma, Hodgkin lymphoma) or carcinomas (e.g., nasopharyngeal carcinoma). HBV and HCV: cause of 70% to 85% of hepatocellular carcinomas worldwide. • Oncogenic effects are multifactorial; dominant effect seems to be immunologically mediated chronic inflammation, hepatocellular injury, and reparative hepatocyte proliferation. • HBx protein of HBV and the HCV core protein can activate signal transduction pathways that also may contribute to carcinogenesis. H. pylori: implicated in gastric adenocarcinoma and MALToma. • Pathogenesis of H. pylori -induced gastric cancers is multifactorial including chronic inflammation and reparative gastric cell proliferation. • H. pylori pathogenicity genes, such as CagA, also may contribute by stimulating growth factor pathways. • Chronic H. pylori infection leads to polyclonal B-cell proliferations that may give rise to a B-cell lymphoma (MALToma) of the stomach as a result of accumulation of mutations.

Hypertrophic osteoarthropathy

Hypertrophic osteoarthropathy is encountered in 1% to 10% of patients with lung carcinoma. Rarely, other forms of cancer are involved. This disorder is characterized by (1) periosteal new bone formation, primarily at the distal ends of long bones, metatarsals, metacarpals, and proximal phalanges; (2) arthritis of the adjacent joints; and (3) clubbing of the digits . Although osteoarthropathy is seldom seen in noncancer patients, clubbing of the fingertips may be encountered in patients with liver diseases, diffuse lung disease, congenital cyanotic heart disease, ulcerative colitis, and other disorders. The cause is unknown.

What are pro-angiogenic factors that turn on the angiogenic switch

Hypoxia stabillizes HIF1a -> activates VEGF and bFGF ->stimulates prolfieration of endothelial cells Driver mutations favor angiogenesis (loss pf P53 -> more permissive for angiogenesis or GOF mutation in RAS or MYC -> upregulation VEGF production) Many proteases release bFGF from the ECM, which constitutes a storage site for this factor, while other proteases release anti-angiogenic factors such as angiostatin and endostatin through proteolytic cleavage of plasminogen and collagen

What accounts for variation in cancer risk among HPV strains

In benign warts, the HPV genome is maintained in a nonintegrated episomal form, while in cancers the HPV genome is integrated into the host genome, suggesting that integration of viral DNA is one factor. Pattern of integration is clonal (alsways interupts within E1/E2 open reading frame) -E6 degrades p53 and stimulates telomerase reverse transcriptase (TERT) which imortalizes cells -E7 complements E6 and speeds cells through G1/S cell cycle checkpoint by binding to RB, displacing E2F, and inactivating CKD inhibitors p21 and p27

What is needed for NK cells to kill tumor cells

In experimental systems, natural killer (NK) cells and activated macrophages are capable of killing tumor cells. After activation with interleukin (IL)-2 and IL-15, NK cells can lyse a wide range of human tumors, including those that are nonimmunogenic for T cells due to loss of expression of MHC class I molecules. The ability of NK cells to kill tumor cells requires no prior sensitization, suggesting that they might constitute a first line of defense.

How does P53 induce cell cycle arrest

In late G1 too much P53 -> transcription of CDKN1A gene (encodes CDK inhibitor p21) -> maintains RB as active so cell cannot progress from G1 to S. Also induces proteins like GADD45 to enhance DNA repair

What four genes regulate phosphorylation of RB

In most cancers, the G 1 -S checkpoint is defective as a result of mutation of one of four genes that regulate the phosphorylation of RB; these genes are RB, CDK4, the genes encoding cyclin D proteins, and CDKN2A (p16) The current paradigm is that loss of normal cell cycle control is central to malignant transformation and that at least one of four key regulators of the cell cycle (p16/INK4a, cyclin D, CDK4, RB) is dysregulated in the vast majority of human cancers .

What is the benefit of having a mutation in the nonreceptor tyrosine kinase JAK2

JAK2 participates in the JAK/STAT signaling pathway, which transduces mitogenic signals from growth factor and cytokine receptors that lack tyrosine kinase activity. JAK/STAT activation alters the expression of target genes that bind STAT transcription factors. Several myeloid neoplasms are frequently associated with activating point mutations in JAK2 that relieve the tumor cells of their normal dependence on hematopoietic growth factors such as erythropoietin

Why can individual tumor cells survive and not apoptose

Loss of adhesion in normal cells leads to induction of apoptosis, but free tumor cells are resistant to this form of cell death (termed anoikis, meaning without a home), in part because of expression of other integrins that mitigate the loss of adhesion to ECM, apparently by transmitting signals that promote cell survival. Additionally, the matrix itself is modified in ways that promote invasion and metastasis. For example, cleavage of the basement membrane proteins collagen IV and laminin by MMP-2 or MMP-9 generates novel sites that bind to receptors on tumor cells and stimulate migration.

How does p53 related to apoptosis

Loss of p53 function prevents the upregulation of PUMA, a pro-apoptotic BH3-only protein, in response to DNA damage and other stresses, allowing cells to survive that otherwise would be killed.

What does the term "mutator phenotype" mean

Loss-of-function mutations affecting DNA repair genes contribute to carcinogenesis indirectly by impairing the ability of the cell to recognize and repair nonlethal genetic damage in other genes. As a result, affected cells acquire mutations at an accelerated rate, a state referred to as a mutator phenotype that is marked by genomic instability.

Why is angiogenesis important in cancer

Maximal distance of growth without this is 1-2mm. Endothelial cells make insulin-like growth factors and PDGF to help cancer cells grow.

What is chromothrypsis

Means "chromosome shattering"; Chromothrypsis is observed in 1% to 2% of cancers as a whole and is particularly common in osteosarcomas and gliomas. It appears to result from a single event in which dozens to hundreds of chromosome breaks occur in a single chromosome or several chromosomes. The genesis of these breaks is uncertain, but DNA repair mechanisms are activated that stitch the pieces together in a haphazard way, creating many rearrangements, deletions, and even amplifications

How does TP53 work Guardian of the genome

Most frequently mutated gene in human cancers tumor suppressor gene that induces transient cell cycle arrest, senescence (permenant arrest), or apoptosis most mutations are somatic (not germline) but an inherited mutation is called Li-Fraumeni syndrome (more likely to get cancer at younger age) MDM2 and related proteins stimulate degredation of p53. Some sarcomas have MDM2 gene amplification E6 protein binds to p53 and promotes its degredation (viral oncoprotein, seen in high-risk HPVs) In nonstressed, healthy cells, p53 is held at bay through its aforementioned association with MDM2, an enzyme that ubiquitinates p53, leading to its degradation by the proteasome. As a result, p53 is virtually undetectable in normal cells. In stressed cells, however, p53 is released from the inhibitory effects of MDM2 via two major mechanisms (DNA damage/hypoxia -> ATM and ATR phosphorylate p53 and MDM2 so p53 accumulates) or (oncogenisc stress -> increased p14/ARF -> binds to MDM2 and displaces p53) It appears that the affinity of p53 for its binding sites in the promoters and enhancers of DNA repair genes is higher than its affinity for binding sites in pro-apoptotic genes. Thus the DNA repair pathway is stimulated first as p53 begins to accumulate. TP53 mutants make cells resistant to irridiation/chemo that induces apoptosis by DNA damage. Also, cells with TP53 mutation acquire mutator phenotype that can make them resistant to cancer therapy in other ways

Explain oncometabolism

Mutations in Krebs cycle genes that alter gene expression Mutant IDH makes 2-hydroxyglutarate (oncometabolite) which inhibits TET family of enzymes that methylate things. So, loss of TET leads to abnormal DNA methylation patterns so cancer genes are misexpressed, so cells transform and oncogenesis begins

What are driver and initiating mutations? What are passenger mutations?

Mutations that contribute to the acquisition of cancer hallmarks are referred to as driver mutations. The first driver mutation that starts a cell on the path to malignancy is the initiating mutation, which is typically maintained in all the cells of the subsequent cancer. However, because no single mutation appears to be fully transforming, development of a cancer requires that the "initiated" cell acquire a number of additional driver mutations, each of which also contributes to the development of the cancer Mutations that lead to genomic instability not only increase the likelihood of acquiring driver mutations, but also greatly increase the frequency of mutations that have no phenotypic consequence, so-called passenger mutations, 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 passenger mutations.

Give an example of a gene that can be a suppressor in one lineage and an oncogene in another

NOTCH1 gene is one of the most commonly mutated tumor suppressor genes in squamous cell carcinoma of the skin (in which the mutations result in loss of function and lead to impaired differentiation) and is also the most commonly mutated oncogene in T-cell acute lymphoblastic leukemia (in which mutations in different parts of the gene result in gain of function and drive the expression of pro-growth genes such as MYC ).

What defines a neoplasm

Neoplasia means "new growth," and the collection of cells and stroma composing new growths are referred to as neoplasms . Tumor originally described swelling caused by inflammation, but is now equated with neoplasm. a neoplasm is defined as a genetic disorder of cell growth that is triggered by acquired or less commonly inherited mutations affecting a single cell and its clonal progeny.

Give an example of local hypermethylation of DNA to silence tumor suppressor genes

One of several examples of a tumor suppressor gene that is hypermethylated in several cancers is CDKN2A, which you will recall is a complex locus that encodes two tumor suppressors, p14/ARF and p16/INK4a, that enhance p53 and RB activity, respectively. Cancers can also have global changes in DNA methylation. Can also have changes in histone positioning or posttranslational modifications (so-called histone marks)

What are some disorders associated with homologous recombination defects

Other types of DNA damage, particularly covalent DNA cross-links and double-stranded DNA breaks, are repaired through a complex process called homologous recombination. Several disorders caused by defects in homologous recombination factors are associated with an increased risk of cancer, as follows: Bloom syndrome- loss of function mutation in helicase. Increased cancer risk Ataxia telangiectasia- autosomal recessive; defect in ATM (gene encodes kinase upstream of p53); see neurodegneration and radiation hypersensistivity. Predisposed to leukemia and lymphoma Fanconi anemia and familial breast cancer are also related to defects in genes for homologous recombination repair

How does p53 induce apoptosis

P53 directs transcription of pro-apoptotic genes Bax and PUMA, pushing cell towards intrinsic (mitochondrial) pathway

How is PI3k/AKT involved in Warburg effect

PI3K/AKT signaling upregulates the activity of glucose transporters and multiple glycolytic enzymes, thus increasing glycolysis; promotes shunting of mitochondrial intermediates to pathways leading to lipid biosynthesis; and stimulates factors that are required for protein synthesis.In addition, receptor tyrosine kinases phosphorylate and inhibit pyruvate kinase, which catalyzes the last step in the glycolytic pathway, the conversion of phosphoenolpyruvate to pyruvate. This creates a damming effect that leads to the buildup of upstream glycolytic intermediates, which are siphoned off for synthesis of DNA, RNA, and protein.

What does PTEN do (think frequent benign skin growths and increased incidence of epithelial cancers aka Cowden sydrome)

Phosphatase and tensin homologue (PTEN) is a membrane-associated phosphatase encoded by a gene on chromosome 10q23 TEN acts as a tumor suppressor by serving as a brake on the PI3K/AKT signaling cascade. PTEN gene function is lost in many cancers through deletion, deleterious point mutations, or epigenetic silencing.

What are precursor lesions

Precursor lesions are defined by localized morphologic changes that identify a field of epithelium that is at increased risk for malignant transformation. These changes may take the form of hyperplasia, metaplasia, or dysplasia

What do cyclin-dependent kinases do

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. The CDK-cyclin complexes phosphorylate crucial target proteins that drive cells forward through the cell cycle. While cyclins arouse the CDKs, CDK inhibitors, of which there are many, silence the CDKs and exert negative control over the cell cycle ( Table 7.6 ). Expression of these inhibitors is downregulated by mitogenic signaling pathways, thus promoting the progression of the cell cycle.

Key concepts for oncogenes, oncoproteins, and unregulated cell proliferation

Proto-oncogenes: normal cellular genes whose products promote cell proliferation. Oncogenes: mutated or overexpressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth-promoting signals. Oncoprotein: a protein encoded by an oncogene that drives increased cancer cell proliferation, which may result from a variety of aberrations. • Constitutive expression of growth factors and their cognate growth factor receptors, setting up an autocrine cell signaling loop. • Mutations in growth factor receptors, nonreceptor tyrosine kinases, or downstream signaling molecules that lead to constitutive signaling, such as: • Activation of the EGF receptor tyrosine kinase by point mutations (lung cancer), activation of the HER2 receptor tyrosine kinase by gene amplification (breast cancer), and activation of the JAK2 tyrosine kinase by point mutations (myeloproliferative neoplasms). • Activation of the ABL nonreceptor tyrosine kinase by chromosomal translocation and creation of a BCR-ABL fusion gene (chronic myeloid leukemia, acute lymphoblastic leukemia). • Activation of RAS by point mutations (many cancers). • Activation of PI3K and BRAF serine/threonine kinases by point mutations (many cancers). • Increased expression of MYC, a master transcription factor that regulates genes needed for rapid cell growth by deregulation through chromosomal translocations (Burkitt lymphoma, other hematologic malignancies), gene amplication (neuroblastoma), and increased activity of upstream signaling pathways (many cancers). • Mutations that increase the activity of cyclin-dependent kinase 4 (CDK4)/D cyclin complexes, which promote cell cycle progression

What are the two major downstream signaling arms of the receptor tyrosine kinase signaling pathway and what are their relevance to cancer

Receptor tyrosine kinase activation stimulates RAS and two major downstream signaling "arms," the MAPK cascade and the PI3K/AKT pathway. In line with the importance of these pathways in mediating cell growth, RAS, PI3K, and other components of these pathways are frequently involved by gain-of-function mutations in different types of cancer. Of interest, when RAS mutations are present in a tumor, activating mutations in receptor tyrosine kinases are almost always absent, at least within the dominant tumor clone, implying that in such tumors activated RAS can completely substitute for tyrosine kinase activity. Point mutations of RAS family genes constitute the most common type of abnormality involving proto-oncogenes in human tumors. RAS proteins are membrane-associated small G proteins that flip between excited signal-transmitting (bound to GTP) to quiescent state (bound to GDP). Stimulation of receptor tyrosine kinases by growth factors leads to exchange of GDP for GTP and consequent RAS activation. GTPase-activating proteins (GAPs) prevent uncontrolled RAS activity (they terminate signal transduction)

What does STK11 do

STK11 has pleiotropic effects on multiple facets of cellular metabolism including glucose uptake, gluconeogenesis, protein synthesis, mitochondrial biogenesis, and lipid metabolism. Sporadic STK11 loss-of-function mutations are found in diverse carcinomas, a finding pointing to the important role of altered cellular metabolism in the establishment and maintenance of the transformed state

What is pseudomyxoma peritonei

Seeding of body cavities and surfaces occurs when a malignant neoplasm penetrates into a natural "open field" lacking physical barriers. Most often involved is the peritoneal cavity ( Fig. 7.13 ), but any body cavity—pleural, pericardial, subarachnoid, and joint spaces—may be affected. Such seeding is particularly characteristic of carcinomas arising in the ovaries, which often spread to peritoneal surfaces, producing a heavy cancerous coating. Remarkably, the tumor cells may remain confined to the surface of the abdominal viscera without penetrating into the substance. Sometimes, mucus-secreting appendiceal carcinomas or ovarian carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass referred to as pseudomyxoma peritonei .

What are the eight hallmarks of cancer

Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Altered cellular metabolism (Warburg effect) Evasion of apoptosis Limitless replicative potential (immortality) Sustained angiogenesis Ability to invade and metastasize Ability to evade the host immune response Genomic instability and cancer-promoting inflammation are considered enabling characteristics (promote cellular transformation and subsequent tumor progression)

Why is autophagy a friend or foe in cancer

Severe nutrient deprivation -> autophagy -> dormancy -> cell resistant to therapies Pathways that induce autophagy aka tumor suppressor pathways are disabled in cancer. Loss of autophagy enhances tumor growth

What is haploinsufficiency

Sometimes loss of only a single tumor suppressor gene allele (a state termed haploinsufficiency) reduces the quantity of the encoded protein enough to release the brakes on cell proliferation and survival. Such a finding indicates that two "doses" of the gene are essential for normal function.

How does the TGF-beta pathway relate to cancer

TGF-B -> stimulates SMAD signaling -> turn on antiproliferative genes and turn off proliferative genes -> decreased phosphorylation of RB and cell cycle arrest

Name an example of nonreceptor tyrosine kinase relevant to cancer

The ABL tyrosine kinase gene translocates from chromosome 9 to 22 where it fuses with the BCR gene, making BCR-ABL protein with constitutive tyrosine kinase activity

Describe the philadelphia chromosome

The Philadelphia chromosome, characteristic of CML and a subset of B-cell acute lymphoblastic leukemias ( Chapter 13 ), provides the prototypic example of a chromosomal rearrangement that creates a fusion gene encoding a chimeric oncoprotein. In this instance the two chromosome breaks lie within the ABL gene on chromosome 9 and within the BCR (b reakpoint c luster r egion) gene on chromosome 22 (see Fig. 7.23 ). Nonhomologous end-joining then leads to a reciprocal translocation that creates an oncogenic BCR-ABL fusion gene on the derivative chromosome 22 (the so-called Philadelphia chromosome). BCR-ABL fusion genes encode chimeric BCR-ABL proteins with constitutive tyrosine kinase activity.

What is the relevance of CAR-T cells?

The ability of CTLs to kill tumor cells independent of other cell types and factors underlies the ferocious antitumor activity of CTLs engineered to express chimeric antigen receptors (so-called CAR-T cells) against lineage-specific surface antigens found on certain tumors. For example, CAR-T cells specific for B-cell antigens are highly active against B-cell tumors but also annihilate normal B cells and release sufficient inflammatory cytokines to cause substantial morbidity and sometimes the death of the patient.

PTHrP important facts

The humoral factor that is most commonly associated with paraneoplastic hypercalcemia is parathyroid hormone-related protein (PTHRP). As its name implies, PTHRP has partial structural homology to parathyroid hormone (PTH). PTHRP and PTH bind to the same G protein-coupled receptor, known as the PTH/PTHRP receptor (often referred to as PTH-R or PTHRP-R), and share some, but not all, biologic activities. Like PTH, PTHRP increases bone resorption and renal calcium uptake, while inhibiting renal phosphate transport, effects that raise serum calcium levels. In contrast to PTH, PTHRP is produced in small amounts by many normal tissues, including epithelial cell types such as keratinocytes, which may explain the relatively frequent association of squamous cell carcinomas with PTHRP-induced hypercalcemia. In addition to PTHRP, several other factors, such as IL-1, TGF-α, TNF, and dihydroxyvitamin D, have been causally implicated in the hypercalcemia of malignancy.

How do you stage a cancer

The staging of solid cancers is based on the size of the primary lesion, whether it has spread to regional lymph nodes, and the presence or absence of blood-borne metastases. The major staging system currently in use is the American Joint Committee on Cancer Staging. This system uses a classification called the TNM system — T for primary tumor, N for regional lymph node involvement, and M for metastases. TNM staging varies for specific forms of cancer, but there are general principles. The primary lesion is characterized as T1 to T4 based on increasing size. T0 is used to indicate an in situ lesion. N0 would mean no nodal involvement, whereas N1 to N3 would denote involvement of an increasing number and range of nodes. M0 signifies no distant metastases, whereas M1 or sometimes M2 indicates the presence of metastases and some judgment as to their number.

Name some things that can bind to RB pocket and inactivate RB

The transforming proteins of several oncogenic animal and human DNA viruses also neutralize the growth inhibitory activities of RB. Of greatest relevance to human cancer, polyomavirus large T antigens and E7 proteins from high-risk types of HPV (such as HPV16) bind to hypophosphorylated RB through the same "pocket" that RB uses to bind and sequester E2F transcription factors. Binding of the viral proteins thus inactivates RB and releases E2F transcription factors, freeing them to cause cell cycle progression.

How do cancer cells degrade basement membrane and connective tissue

Tumor cells may accomplish this by secreting proteolytic enzymes or by inducing stromal cells (e.g., fibroblasts and inflammatory cells) to do so. Many different proteases such as matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator are overexpressed in tumors and have been implicated in tumor cell invasion . MMPs regulate tumor invasion not only by remodeling the basement membrane and interstitial connective tissue, but also by releasing factors that contribute to the malignant behavior of cancers. For example, MMP-9, a gelatinase that cleaves type IV collagen found within the epithelial and vascular basement membrane, also stimulates the release of VEGF from ECM-sequestered pools and generates collagen and proteoglycan cleavage products with chemotactic, angiogenic, and growth-promoting effects.

What is p53

Tumor suppressor that is altered in the majority of cancers. Induced by DNA damage. Causes cell cycle arrest by upregulating the CDK inhibitor p21. Induces apoptosis by upregulating BAX and other pro-apoptotic genes

How does chronic inflammation predispose to cancer

Tumors arising in the context of chronic inflammation are mostly carcinomas, but also include mesothelioma and several kinds of lymphoma. As with any cause of tissue injury, these disorders are accompanied by a compensatory proliferation of cells that serves to repair the damage. In some cases, chronic inflammation may increase the pool of tissue stem cells, which may be particularly susceptible to transformation. Additionally, activated immune cells produce reactive oxygen species that may damage DNA and inflammatory mediators that may promote cell survival, even in the face of genomic damage. Patients who are immunodeficient, particularly those with deficits in T-cell immunity, are at increased risk for cancer, especially types caused by oncogenic viruses, presumably because these individuals have a higher than normal incidence of chronic infection with viruses. These virus-associated tumors include lymphomas, certain carcinomas, and some sarcomas and sarcoma-like proliferations.

what is the Knudson two-hit hypotesis of oncognesis

Two mutations involving both alleles of a gene are required to produce the mutated phenotype (in this case RB -> retinoblastoma) In the case of retinoblastoma, if the germeline allele is defective, the disease is inherited as an autosomal dominant trait (germline mutation in tumor suppressor gene RB)

What does UV radiation do to DNA and how does the body fix it

UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is repaired by the nucleotide excision repair system. Several genes are involved in nucleotide excision repair. Inherited loss-of-function mutations in any of these genes gives rise to a syndrome called xeroderma pigmentosum that is marked by an extraordinarily high risk of skin cancers, specifically squamous cell carcinoma and basal cell carcinoma.

How does PI3K normally function

Under normal circumstances, following receptor tyrosine kinase activation, PI3K is recruited to plasma membrane-associated protein complexes. Here, like BRAF, it activates a cascade of serine/threonine kinases, including AKT. AKT phosphorylates more than 150 proteins and constitutes a major signaling node. Its substrates include key regulators of protein synthesis (mTOR) and apoptosis (BAD, FOXO transcription factors, MDM2, and IAP, all described elsewhere).

Explain Burkitt lympoma in the context of gene translocation

Virtually all Burkitt lymphomas have a translocation involving chromosome 8q24, where the MYC gene resides, and one of the three chromosomes that carry an immunoglobulin gene. At its normal locus, MYC is tightly controlled and is most highly expressed in actively dividing cells. In Burkitt lymphoma the most common translocation moves the MYC -containing segment of chromosome 8 to chromosome 14q32placing it close to the immunoglobulin heavy chain (IGH) gene. The genetic notation for the translocation is t(8;14)(q24;q32). The molecular mechanisms of the translocation-mediated overexpression of MYC are variable, as are the precise breakpoints within the MYC gene. In most cases the translocation removes regulatory sequences of the MYC gene and replaces them with the control regions of the IGH gene, which is highly expressed in B cells. The MYC coding sequences remain intact, and the MYC protein is constitutively expressed at high levels.

What is oncogene addition

When tumor cells are highly dependent on the activity of one oncoprotein, like the BCR-ABL tyrosine kinase pathway in CML. Targeting BCR-ABL however can allow for CML stem cells to still persist that do not require BCR-ABL to survive, so therapy with BCR-ABL must be continued indefinitely or full-blown leukemia will return

Aflatoxin B1-associated hepatocellular carcinoma

atoxin B 1 -associated hepatocellular carcinomas tend to have a particular mutation in TP53 , a G:C→T:A transversion in codon 249 that produces an arginine-to-serine substitution in the p53 protein that interferes with its function. In contrast, TP53 mutations are infrequent in liver tumors from areas where aflatoxin contamination of food does not occur, and few of these mutations involve codon 249.

What are the places that dna breaks occur in B and T cells

double-stranded DNA breaks must occur simultaneously in at least two places in the genome, and the free DNA ends must then be joined to create two new derivative chromosomes. In lymphoid cells, most of these molecular misadventures are believed to occur during attempts at normal antigen receptor gene recombination (which occurs in both B- and T-cell progenitors) or class-switch recombination (which is confined to antigen-stimulated mature B cells). The affected genes are diverse, but as with translocations involving MYC, the net effect is overexpression of some protein with oncogenic activity.

What alteration is common in chronic lymphocytic leukemia

eletions affecting miR-15 and miR-16 are among the most frequent genetic lesions in chronic lymphocytic leukemia, a common tumor of older adults ( Chapter 13 ). In this tumor, loss of these mIRs leads to upregulation of the anti-apoptotic protein BCL-2, enhancing tumor cell survival. Conversely, overexpression of other miRs represses the expression of tumor suppressor genes; such miRs promote tumor development and are referred to as onco-miRs. One example of an onco-miR is miR-155, which is overexpressed in many human B-cell lymphomas and indirectly upregulates a large number of genes that promote proliferation, including MYC .

What are the four classes of genes that are principle targets of cancer-causing mutations

growth-promoting proto-oncogenes, growth-inhibiting tumor suppressor genes, genes that regulate programmed cell death (apoptosis), and genes that are responsible for DNA repair

How do cyclins effect cell cycle progression

he "decision" of a cell to progress from G 1 into S is of great importance, as once a cell enters S phase it is obligated to complete mitosis. High levels of CDK4/cyclin D, CDK6/cyclin D, and CDK2/cyclin E complexes lead to hyperphosphorylation and inhibition of RB, releasing E2F transcription factors that drive the expression of genes that are needed for progression to S phase. Growth inhibitors upregulate CDK inhibitors

Which UV causes cutaneous cancer

he UV portion of the solar spectrum can be divided into three wavelength ranges: UVA (320-400 nm), UVB (280-320 nm), and UVC (200-280 nm). Of these, UVB is believed to be responsible for the induction of cutaneous cancers. UVC, although a potent mutagen, is not considered significant because it is filtered out by the ozone layer surrounding the earth (hence concerns about ozone depletion). UVB light is carcinogenic because of its ability to cause pyrimidine dimers to form in DNA Absorption of the energy in a photon of UV light by DNA produces a chemical reaction that leads to covalent cross-linking of pyrimidine bases, particularly adjacent thymidine residues in the same strand of DNA. This distorts the DNA helix and prevents proper pairing of the dimer with bases in the opposite DNA strand. The importance of the nucleotide excision repair pathway of DNA repair is most graphically illustrated by the high frequency of cancers in individuals with the hereditary disorder xeroderma pigmentosum In humans, for reasons that are not clear, there is a hierarchy of tissue vulnerability to radiation-induced cancers. Most frequent are myeloid leukemias

What are the potential functions of tumor suppressor genes

he protein products of tumor suppressor genes may function as transcription factors, cell cycle inhibitors, signal transduction molecules, cell surface receptors, and regulators of cellular responses to DNA damage. Some tumor suppressors can cause cells to enter postmitotic differentiated pool withou replicative potential, or can induce apoptosis

What prevents benign tumors from local invasion

hey usually develop a rim of compressed fibrous tissue called a capsule that separates them from the surrounding normal tissue. The tumor capsule consists of extracellular matrix (ECM) deposited by stromal cells such as fibroblasts, which are activated by hypoxic damage resulting from the pressure of the expanding tumor. Such encapsulation creates a tissue plane that makes the tumor discrete, readily palpable, movable (nonfixed), and easily excisable by surgical enucleation Exception to rules include hemangiomas which are often unencapsulated and permeate site

How does epithelial to mesenchymal transition help cancer cells metastasize

in many other epithelial cancers it is hypothesized that E-cadherin expression is silenced, at least transiently, through a process called epithelial-mesenchymal transition (EMT). It is postulated that EMT is integral to the metastasis of carcinomas, particularly breast and prostate cancers. EMT is controlled by the transcription factors SNAIL and TWIST and is defined not only by the downregulation of epithelial markers (e.g., E-cadherin) but also by the concomitant upregulation of mesenchymal markers (e.g., vimentin and smooth muscle actin), changes that are believed to favor the development of a promigratory phenotype that is essential for metastasis.

What is a hallmark of mismatch-repair defects

microsatellite instability. Microsatellites are tandem repeats of one to six nucleotides found throughout the genome. In normal people the length of these microsatellites remains constant. However, if mismatch repair is defective, these satellites are unstable and increase or decrease in length, creating mutated alleles.

What's the differnece between initation and promotin in cancer

nitiation results from exposure of cells to a sufficient dose of a carcinogenic agent. It causes permanent DNA damage (mutations). Promoters can induce tumors to arise from initiated cells, but they are not tumorigenic by themselves. Application of promoters leads to proliferation and clonal expansion of initiated (mutated) cells. Driven to proliferate, subclones of the initiated cells suffer various additional mutations, and eventually a cancerous clone with all the hallmark characteristics emerges.

What do members of the INK4/ARF family do (CDKN2A-C)

p16/INK4a binds to cyclin D-CDK4 and promotes the inhibitory effects of RB. p14/ARF increases p53 levels by inhibiting MDM2 activity

How does a loss of p53 contribute to genetic instability

p53 protects the genome from potentially oncogenic damage by arresting cell division to provide time for repair of DNA damage and by initiating apoptosis in irreparably damaged cells. Cancers with loss of p53 function not only accumulate point mutations but also are strongly associated with aneuploidy, which may take the form of deletions, amplifications, and complex chromosomal rearrangements. These genomic aberrations may occur in cells with defective telomeres during break-fusion-breakage cycles or may be created by other types of chromosomal "catastrophes" that lead to DNA breaks in multiple chromosomes. In the absence of p53 function, cells with severely damaged genomes that normally would be eliminated persist and stitch their chromosome back together in an error-prone way using the nonhomologous end-joining pathway. TP53 is the most commonly mutated gene in cancer, and loss of p53 function is thus the preeminent source of genomic instability in cancers

How does MYC relate to the Warburg effect

pro-growth pathways upregulate expression of the transcription factor MYC, which drives changes in gene expression that support anabolic metabolism and cell growth. Among the most important metabolic factors that are upregulated by MYC are multiple glycolytic enzymes and glutaminase, which is required for mitochondrial utilization of glutamine, another important source of intermediates needed for biosynthesis of cellular components

Concept of BRAF gain-of-function mutation in treatment of tumors

t is now appreciated that histopathologically distinct cancers may harbor the same gain-of-function mutation in the serine/threonine kinase BRAF, a component of the RAS signaling pathway ( Fig. 7.48 ). In principle, all of these diverse "BRAFomas" are candidates for treatment with BRAF inhibitors. However, clinical studies have shown that the effectiveness of BRAF inhibitors (for reasons that remain to be determined) vary widely depending on histologic subtype: hairy cell leukemias with BRAF mutations typically show sustained responses, melanomas respond transiently, and colon carcinomas respond little, if at all, emphasizing the value of morphologic diagnosis

What does CDKN2A gene encode

the CDKN2A gene encodes two protein products: the p16/INK4a cyclin-dependent kinase inhibitor, which blocks CDK4/cyclin D-mediated phosphorylation of RB, thereby reinforcing the G 1 /S checkpoint; and p14/ARF, which activates the p53 pathway by inhibiting MDM2 and preventing destruction of p53.

What is the main function of mitochondria in a growing cell

the main metabolic function of mitochondria in growing cells is not to generate ATP, but rather to carry out reactions that generate intermediates that can be diverted for use as precursors in the synthesis of cellular building blocks. For example, lipid biosynthesis requires acetyl coenzyme A (acetyl-CoA), and acetyl-CoA is largely synthesized in growing cells from intermediates such as citrate that are generated in mitochondria.

How are E-cadherin and β-catenin related

β-catenin binds to cytoplasmic tail of E-cadherin. Loss of cell-cell contact disrupts this interaction so β-catenin can translocate to nucleus and stimulate genes that cause proliferation. Re-establishment of connections sequesters β-catenin

How can translocations activate proto-oncogenes

• By promoter or enhancer substitution, in which the translocation results in overexpression of a proto-oncogene by swapping its regulatory elements with those of another gene, typically one that is highly expressed. • By formation of a fusion gene in which the coding sequences of two genes are fused in part or in whole, leading to the expression of a novel chimeric protein with oncogenic properties.

HNPCC syndrome Xeroderma pigmentosum

• Patients with HNPCC syndrome have defects in the mismatch repair system, leading to development of carcinomas of the colon. These patients' genomes show microsatellite instability, characterized by changes in length of short repeats throughout the genome. • Patients with xeroderma pigmentosum have a defect in the nucleotide excision repair pathway and are at increased risk for the development of cancers of the skin exposed to UV light because of an inability to repair pyrimidine dimers.