Exam 2: Cancer Flashcards

Question

Natural Barriers

Answer 1

**Epithelial cell adherence & presence of ECM** ⇒ natural barrier against invasion & metastasis Malignant cells develop ways of **untethering attachments**

Answer 2

* **Cell adhesion molecules (CAMs)** * Involved in cell-cell & cell-matrix adhesions * Form dynamic connections ⇒ links cell function & growth to adhesion * **Growing epithelial cells coupled by E-cadherin** * Interaction results in _anti-mitotic signal_ ⇒ **contact inhibition** * The stop of growth once cells touch

Answer 3

* **Detachment** * Tumor cells untheter from ECM * Infiltrate neighboring tissues * Loss of contact inhibition * **Secretion of metalloproteases @ invading edge** * Helps break down ECM * Remodels basement membrane * Facilitates invasion * **Allows cancer to penetrate body cavities and metastasize** * Blood vessels ⇒ **hematogenous spread** * **Lymphatic spread**

Answer 4

Cancer cells break away from the primary tumor and establish growth at a distant site ⇒ **direct seeding** * Many cancers tend to **metastasize to a specific site or organ** * **Can** **penetrate a body cavity** * Peritoneal, pleural, or pericardial spaces * Can block drainage sites or actively secrete fluids ⇒ fluid accumulation * **Highly inefficient process** * \<0.01% of detached, circulationg tumor cells ⇒ secondary tumor * Still ~ 30% of new solid tumors have metastasis * **Cells @ secondary tumor represent a distinct subpopulation of cells** * Undergone significant selective pressures * Demonstrate clinically significant differences * ↑↑ rate of mutation ⇒ rapid phenotypic diversification * Can confer resistance to therapeutic interventions * **Undetected micrometastases** may remain dormant and lead to recurrance after treatment

Answer 5

* ID the lymph node to which cancer cells are most likely to have spread ⇒ **sentinel node** * Mapped using colored dye or radioactive tracer injected into primary tumor * Node removed and evaluated for metastasis * Can help in staging & avoid extensive LN removal

Answer 6

* Spread via blood vessels * Often results in metastasis to bone, lung, liver, or brain * Venous invasion more common than arterial

Answer 7

Favorable interactions between **metastatic tumor cells (the seed)** and **organ microenvironment (the soil)** ⇒ **organ-preference patterns during metastasis** * Ex. bone is a common site for metastasis * Constant growth and cell turnover * Osteoblasts produce abundant cytokines and non-collagen proteins * Act as fertile "soil" * Allows malignant cells to survive, proliferate, spread, and invade bone matrix

Answer 8

Multiple coordinated processes during interphase and M phase: * Cell growth * DNA replication * Distribution of duplicated chromosomes * Cell division

Answer 9

_4 successive phases:_ 1. Gap 1 ⇒ **G₁ phase** 2. Synthesis ⇒ **S phase** 3. Gap 2 ⇒ **G₂ phase** 4. Mitosis ⇒ **M phase**

Answer 10

**G₀** * _Usually due to lack of growth factors or nutrients_ * Some cells remain in G₀ once they reach maturity * Ex. nerve cells, cardiac myocytes * Some enter semi-perminant G₀ and will only divide under specific circumstances * Ex. liver and kidney parenchymal cells

Answer 11

**Checkpoints** and **feedback controls** prevent entry into the next phase until all events of preceding phase have been completed correctly. Ensures that incomplete/damaged chromosomes are not replicated and passed onto daughter cells.

Answer 12

_Depend on interaction of two key components:_ 1. **Cyclin-dependent kinases (Cdks)** * _Serine/threonine kinases_ * Provide the enzyme activity * Constitutively expressed * Function dependent on cyclin binding 2. **Cyclins** * _Determines substrate specificity_ * [Cyclin] cycles up and down during the cell cycle * Presence/absence regulated by both _synthesis and degradation pathways_

Answer 13

**Controls commitment to the cell cyle.** * _Assesses:_ * **Appropriate growth factors** * **Adequate size** * **Adequate energy stores** * **Intact genome** * _If any criteria are not met_ ⇒ **cell cycle halted until issue resolved** * _If criteria met_ ⇒ **signaling via cyclins and cyclin-dependent kinases (Cdks)** ⇒ pass through restriction point * Becomes _committed_ to cell division * _Once this restriction point passed_, **no additional extracellular signals required**

Answer 14

**Cyclin D-Cdk 4/6 complex** initiates the _release of Rb-dependent cell cycle inhibitory 'brake'_ on the growth factor dependent G1 restriction point controlling transition into the cell cyle. * Entry into S phase blocked by **"hypophosphorylated" retinoblastoma tumor suppressor protein** (Rb, pRb) * _Rb binds and sequesters E2F transcription factors_ * When a cell reaches a _critical size_ in the presence of _specific growth factors and nutrients_ ⇒ **Cyclin D generated** * Cyclin D binds either **Cdk4** or **Cdk6** * **Cyclin D-Cdk 4/6 complex**"_hyperphosphorylates_" **Rb** * Rb no longer able to bind/inhibit E2F components * E2F activates genes needed for transition into S phase and DNA synthesis * **Rb remains hyper-℗ throughout S, G₂, and M phases**

Answer 15

* **Encodes retinoblastoma protein (Rb)** * **Tumor suppressor gene** * **Loss-of-function mutations in RB1** linked to malignancy * Retinoblastoma * Bladder CA * Breast CA * Lung CA * Osteosarcoma * Melanoma * Leukemias

Answer 16

Rb is a target for viral oncoproteins. Ex. **E7 protein of HPV binds and inhibits Rb.**

Answer 17

**Growth factor binding ⇒ Ras/Raf/ERK signaling ⇒ Cyclin D synthesis** * Continues to be made if GF present * **Rapidly degraded** ⇒ [Cyclin D] quickly falls if GF removed * Illustrates the molecular mech of GF dependent proliferation

Answer 18

* Most are **gain-of-function mutations** ⇒ **↑ cyclin D activity** * ↑ transcription of cyclin D * Gene amplification * ↑ stability of mRNA via 3' modifications * ↑ protein function * ↑ protein stability * Inhibition of Cdk inhibitor (CKI) binding * **Implicated in many human cancers** * Overexpression found in \> 50% of human breast CA * CDK4/6 inhibitors used to treat * ↓ risk of breast CA progression or death

Answer 19

**Controls DNA replication.** * Assesses fidelity/completion of DNA replication * Blocks cell cyle if problem detected * Presence of long stretches of ssDNA * Chromome damage

Answer 20

DNA damage or replication fork failure during replication ⇒ **mitotic delay** **Blocks cell cycle at G₁, S phase, and G₂/M checkpoints.** Allows time for DNA repair or stimulates apoptosis if unrepairable. * **Sensor proteins** * Recognize damage * Recruits other modulators to the site * "Marks" the damage * **Up-regulation of inhibitor molecules** * Ex. p53 from TP53 gene * **Down-regulation of stimulatory molecules** * Cdc 25 family

Answer 21

**Tumor suppressor gene** * **_Under normal circumstances:_** * **p53 bound by Mdm2** (ubiquitin ligase) * Targets p53 for proteasomal degradation * Cell has little functional p53 * Allows other components to control cell cycle e.g. growth factors * **_Under conditions of cellular stress:_** ⇒ DNA damage, hypoxia, certain cytokines, metabolic changes, viral infection, telomere shortening, oncogene-based degregulation * **p53 phosphorylated** ⇒ ubiquitylation suppressed ⇒ **p53 stabilized and accumulates in the nucleus**

Answer 22

* **Transcriptional regulator** * Binds both DNA and transcription factors * Halts cell cycle * Can lead to cycle arrest or apoptosis * _p53 actions:_ * **Binds to response elements throughout genome** ⇒ ∆ transcription * **↑ expression of p21** ⇒ potent Cdk inhibitor (CKI) * **Binds Cyclin D-Cdk4/6 and Cyclin E-Cdk2 complexes** * ⊗ transition through G₁ checkpoint * **Transcriptional repression of Cdc 25** * Needed to pass through G₂/M checkpoint * **Binds and inhibits DNA pol sliding clamp** ⇒ ⊗ DNA replication * **Induction of apoptosis** * Via caspase and Bcl2 pathways

Answer 23

**Controls entry into mitosis.** * _Evaluates:_ * **Cell size** * **Protein reserves** * **Intact fully replicated genome** * Problems in the DNA or genome triggers checkpoint ⇒ halts cell cycle until replication completed or damage repaired

Answer 24

**Regulated by Cyclin B-Cdk1 complex.** * **Cyclin B cyclical expression** * Low [Cyclin B] during G₁ and S phase * ↑↑↑↑ [Cyclin B] through G₂ phase and into M phase * Destroyed at the end of mitosis * _During G₂ phase:_ * Cyclin B accumulates * **Cyclin B complexes with Cdk1 (aka "Cdc2")** * **Cdk1** undergoes _two distinct regulatory phosphorylation events_ * **Cyclin H-Cdk7** _activates_ Cdk1 via **℗ at Thr 161** * **Wee1** _inactivates_ Cdk1 via **℗ at Thr 14 and Tyr 15** * Allows inactive Cyclin B-Cdk1 to accumulate through G₂ phase * _Upon entry into mitosis:_ * _Inhibitory ℗'s removed_ by **Cdc25** ⇒ activation of Cyclin B-Cdk1 complex * **Active Cyclin B-Cdk1 complex complex ℗'s downstream targets**

Answer 25

Elicits effects via ℗ of downstream targets: * **Activates condensins** * Helps condense chromosomes * **∆ histones** * **℗ nuclear lamins** * Promotes dissociation of nuclear envelop * **℗ microtubules triggering instability** * Facilitates mitotic spindle formation

Answer 26

**DNA damage ⇒ p53 activation ⇒ p21 ⇒ ⊗ Cdc25** Cyclin B-Cdk1 remains inactive Halts entry into mitosis

Answer 27

Wee1 is an inhibitory kinase * **Often overexpressed in many cancer cells** * Compensates for cells that have lost G1 and S phase checkpoints * Due to loss of p53 or Rb function * **G2/M checkpoint is the major stop point for DNA repair in many cancer cells** * Inhibitors of Wee1 a target for therapeutic intervention * ↑ genomic instability ⇒ cancer cell damage/death

Answer 28

_Regulated at a minimum of 5 steps:_ 1. **Presence/absence of cyclin partner** * Via cyclin transcription/synthesis and regulated degradation 2. **Enabling ℗ events** ⇒ opens catalytic domain of Cdk 3. **Inhibiting ℗ events** ⇒ block Cdk function * Until a phosphatase like Cdc25 triggers the start of S phase 4. **Binding of Cdk inhibitor proteins (CKIs)** 5. **Ubiquitylation and destruction of specific regulatory proteins**

Answer 29

Adds another level of regulation to the cell cycle. * Regulation and actions: * ∆ cell cycle by ⊗ cyclin-Cdk complexes * Transcription * Apoptosis * Migration * Examples: * **p21** * Transcriptional target of p53 * **p15** * Mediates response to TGF-β * Binds to Cyclin D-Cdk4/6 complexes * Results in G1 cell cycle arrest * Inhibits proliferation of cells like T and B lymphocytes

Answer 30

**Controls start of anaphase.** * Occurs near the end of metaphase * **Ensures each pair of sister chromatid is appropriately attached to at least two spindle microtubules arising from opposite poles** * Critical checkpoint ⇒ seperation of sister chromatids irreversible

Answer 31

* **Early embryonic cells constantly replicating** * Do not enter G₀ * **Cell cycle control depends exclusively on post-transcriptional mechanisms** * Involves the regulation of Cdks and ubiquitin ligases

Answer 32

**Clinical tool that determines how fast a population of cells is proliferating.** **# of cells actively in mitosis / total # of cells** * Low mitotic index ⇒ cells dividing slowly * High mitotic index ⇒ cells dividing rapidly * Can be a prognostic factor * Used in clinical decision making to ∆ treatment

Answer 33

* Uses fluorescent DNA-binding dyes * **Allows assessment of # of cells in the cell cycle** * Look @ ratio of cells in G1 and S phase * **Can assess chromosome instability and aneuploidy** * Aneuploidy in cancer tissue seen as a predictor of a poor prognosis

Answer 34

* Detects DNA damage * Recruites other molecules to the damage site * "Mark" the damage * Ex: * **p53** ⇒ upregulates inhibitory molecules * **Cdc25 family** ⇒ downregulates stimulatory molecules

Answer 35

The overall **sequential transition** from a normal cell to a malignant one is called the **multistep process of carcinogenesis**. Cells acquire cancer promoting mutations through spontaneous and environmentally-induced DNA damage.

Answer 36

_Generally encode products which:_ * Directly regulate cell proliferation * Are involved in the repair of damaged DNA * Control programmed cell death or apoptosis These **"driver" mutations** classified as: * **Proto-oncogene** ⇒ promotes growth * **Tumor suppressor gene** ⇒ inhibits growth * **Landscaping genes** ⇒ impacts the cellular microenvironment * Cell adhesion, susceptibility to apoptosis, etc Many **passenger mutations** will also develop. By definition have no phyotypic consequence on the cell.

Answer 37

The normal cellular form of genes that are involved in regulating cell proliferation.

Answer 38

**Mutated, cancer causing forms of proto-oncogenes.** * **Promotes cell growth** * **Gain-of-function** **mutation** in most cases * ↑ function can be due to: * ↑ function of the gene product * ↓ degradation * ∆ gene expression pattern * ∆ in the gene product's function * **Mutation of a single allele required to contribute to tumor formation** * Works in a **dominant manner** within the cell * Usually lethal and rarely inherited ⇒ do not show an inheritance pattern * Result from **somatic mutations** * Many different genes can encode oncoproteins such as: * **Growth factors or mitogens** * **Growth factor receptors** (HER2/neu) * **Signal transducers** (Ras) * **Transcription factors** (Myc) * **Cell cycle regulators** (cyclin D) * **Pro-survival molecules** (Bcl2)

Answer 39

* **Oncogene which can be inherited** * Germline mutation results in constitutive activation of RET * Results in **multiple endocrine neoplasia type 2 (MEN2)**

Answer 40

* Gene encodes receptor tyrosine kinase called **human epidermal growth factor receptor** (HER) * Closely related to EGF receptor * Overexpressed through **gene amplification** * Prompts **ligand independent** signaling via the **Ras-MAPK** **pathway** * Drives cellular proliferation * **Enables constitutive activation of growth factor signaling pathways** * Operates as an oncogenic driver in breast cancer * Acts as both a biomarker and target for therapy

Answer 41

* **Breast CA that overexpress HER2/neu** * More clinically aggressive * Less responsive to hormonal therapy * **Recommended that every invasive breast CA be tested for HER2 mutations** * Also recommend retesting whenever CA recurs or spreas * Genome instability and selective pressures ⇒ ∆ tumor status * **Herceptin** * mAb that targets HER2 * Has improved prognosis for HER2-positive breast CA significantly

Answer 42

* **Small GTPases activated by guanine nucleotide exchange factors (GEFs)** * **Ras** **turns on other proteins** ⇒ transcription of genes involved in regulation of: * Cell growth * Proliferation * Differentiation * Mutations ⇒ production of **activated Ras proteins** _permanently locked into active form_ * Continually activates **MAP kinase pathway** * Leads to cell proliferation * **Represents the most common type of mutation in an oncogene**

Answer 43

* **Critical role in growth factor signaling** * Cyclin D-Cdk4/6 complex * Initiates release of Rb-dependent cell cycle-inhibitory "brake" on G1 checkpoint * **↑ cyclin D function ⇒ ↓ Rb activity** * **Gain-of-function mutations** via: * _Gene amplification_ * _Reciprocal translocation_ * Positions the gene near cis Ig heavy chain enhancer elements * _Chromosomal inversion_ * Brings proto-oncogene close to a strong transcriptional control element * **CKIs can still inhibit the kinase action** * **↑ cyclin D expression drives the cell closer to growth factor independent function**

Answer 44

* Part of the early response genes transiently induced by **RAS/MAPK path following GF stimulation** * Myc protein **promotes transcription of many genes driving cell growth and proliferation** * Ex. cyclin D expression regulated by Myc * Converted to oncogene through _amplification_ or _translocation_ * **Burkett lymphoma** ⇒ most often caused by translocation t(8;14) (q24; q32) * Potential therapy target: * Inactivation of small ubiquitin-like proteins in Myc + cells ⇒ mitotic catastrophe * Pharm uncoupling of bioenergetic pathways involving glucose or glutamine metabolism from Myc-induced accumulation might stop tumor growth

Answer 45

* **ABL1 proto-oncogene** encodes cytoplasmic and nuclear **protein tyrosine kinase** involved in: * Cell differentiation * Cell division * Cell adhesion * Stress response * **Loss of regulatory domain on ABL1 protein converts to oncogene** * Can occur through **reciprocal translocation** * Results in the **Philadelphia chromosome** * New chromosome encodes a _chimeric gene_ - **BCR-ABL** ⇒ exhibits unregulated TK activity * Found in: * Most patients with chronic myelogenous leukemia (CML) * Acute lymphoblastic leukemia (ALL) * Acute myelogenous leukemia (AML) * GI stromal tumors

Answer 46

* Proto-oncogene is an **apoptotic regulator** * Oncogene activated by _chromosome translocation_ in human follicular lymphoma * Oncoprotein * Does not drive cell proliferation * **Instead promotes cell survival** * Can inhibit effectiveness of chemotherapy due to "to live" signal

Answer 47

* Normally: * Inhibits cell proliferation * Act as brakes for the cell cycle * Inhibits formation of tumors * Encodes: * Transcription factors * Cell cycle inhibitors * Signal transduction molecules * Cell surface receptors * Regulators of cellular responses to damage * Cancer often results from a **loss-of-function mutation** * **Only one functional copy needed to prevent cancinogenesis** * Functions in a _recessive fashion_ at cellular level * **Mutations inherited** in _autosomal dominant fashion_

Answer 48

1. Gatekeeper genes 2. Caretaker genes 3. Landscaper genes

Answer 49

**Directly controls cellular growth, differentiation, and apoptosis.** * Normal genes: * **⊗ mitogenic signaling pathways** * Adenomatous polyposis coli (APC) * NF1 * p21 * **⊗ cell cycle progession** * Rb * **Enable genome stability** * p53 * **Provide proapoptotic functions** ⇒ promote tumor suppressor function * p53, BAX * **Mutations directly relieves normal controls** * Promotes outgrowth of cancer cells

Answer 50

**Involved in maintaining the genetic integrity of the cell.** * Regulates: * DNA repair mechanisms * Chromosome segregation * Cell cycle checkpoints * **Mutations result in genome instability** * ↑ frequency of alterations to gatekeeper genes * Examples: * BRCA-1 and BRCA-2 ⇒ breast CA * MSH1, MLH1, and MSH6 ⇒ Hereditary nonpolyposis colon CA

Answer 51

**Impacts the intracellular and extracellular environment of the malignant cell.** * Mutations lead to abnormal extracellular and intracellular environments * Contributes to carcinogenesis * Examples: * E-cadherin ⇒ promotes cell adhesion inhibiting invasion and metastasis * Inhibitors of pro-growth programs for metabolism and angiogenesis * Von-Hippel-Lindau tumor suppressor protein in hypoxic response

Answer 52

* **Mutation in both copies of a tumor suppressor gene needed for carcinogenesis** * Only one functional copy needed to prevent cancers * Someone with an inherited deficit only needs one somatic mutation for carginogenesis

Answer 53

Rare childhood tumor of the retina caused by loss-of-function in both RB1 alleles. * **Sporadic form** * Spontaenous * Occurs unilaterally * **Familial form** * ~30-40% of cases * Inherits one bad copy of RB1 * A single hit causes **loss of heterozygosity** * Tends to develop tumors at an earlier age * More likely to have multifocal unilateral or bilateral retinoblastoma * **Loss of RB1 function results in loss of functional sequestration of transcription factor E2F** * E2F able to bind and promote production of cyclin E * Allows cell to transition through G1 checkpoint in absence of growth factors

Answer 54

**Guardian of the Genome** * **p53 is the most common genetic mutation in human tumors** * **Loss-of-function mutations** found in wide variety of cancers * \> 50% of malignant cells have a p53 mutation * Other cancers have mutations that ∆ p53 function * ↑ Mdm2 expression ⇒ functional p53 deficiency

Answer 55

* **Individual inherits one abnormal copy of the TP53 gene** * 25x greater chance of developing cancer by age 50 * ↑ risk many cancers * Breast CA * ALL * Soft-tissue sarcomas * Osteosarcomas * Adrenocortical carcinoma * Some brain cancers

Answer 56

* BRCA proteins expressed in most cells * **Role in maintaining genome stability through repair of double stranded breaks** * Significant role in breast and ovarian cancer * BRCA-1/BRCA-2 mutation cause 90% of "single gene" breast CA * Penetrance between 30-90% depending on mutation type, genetic and environmental factors * Mutations to these genes rare in sporadic breast cancer * May be due to **EMSY** * Binds and inhibits BRCA-2 * EMSY genes often amplified in sporadic breast cancer resulting in functional inhibition of BRCA-2

Answer 57

Many cancers have mutations in genes responsible for epigenetic regulation. _Can include changes in:_ * DNA methylation * Histone modifiers (writers and erasers) * Histone readers * Chromatin remodelers * MicroRNAs * Other components of chromatin Intergenerational epigenetic inheritance may explain some aspects of cancer heritability.

Answer 58

**Can visibly change the appearance of malignant cells:** * Hyperchromasia * Chromatic clumping * Vesicular nuclear chromatin

Answer 59

* **DNA methyltransferase inhibitor** * ∆ cell epigenetic patterning through prevention of DNA methylation * Used to treat myeloproliferative disorders and ALL

Answer 60

**Environmental exposures** & **host characteristics** can significantly impact the likelihood of developing cancer.

Answer 61

Materials that are known to cause cancer. Classified as: * Physical radiation * Chemical * Biological

Answer 62

* Exposure ↑ risk of cancer * **Non-ionizing radiation** * UV radiation from sunlight * **Ionizing radiation** * Cosmic sources * Nuclear power plant generation * Medical uses like XR and CT * Accounts for 50% per capital radiation dose * **Radon gas** ⇒ greatest exposure to radiation for most people * Tasteless, colorless, odorless gas * Released during decay of uranium in rock and soil * Inhalation can occur during mining * Present in many homes * Seeps up from the ground * Estimated to be 2nd leading cause of lung CA

Answer 63

_Two types:_ 1. **Direct-acting** * Requires no metabolic conversion 2. **Indirect-acting** * Requires metabolic conversion * Usually by CYP450 enzymes Notable chemical carcinogens ⇒ tobacco smoke, aflatoxins, arsenic

Answer 64

* **Contains \> 7,000 chemicals** * 250 known to be harmful * Cyanide, CO, ammonia * **\> 70 can cause cancer** * **Smoking is a leading cause of cancer and associated death** * Lung, esophagus, larynx, mouth, throat, kidney, bladder, liver, pancreas, stomach, cervix, colon, rectum * Smoking 1 PPD ⇒ 150 extra mutations in each lung cell for each year smoked

Answer 65

* **Exposure associated with ↑ risk of liver cancer** * **Family of toxins produced by certain fungi that grow on food products** * Corn, peanuts, cottonseed, tree nuts * Crops can be contaminated * FDA w/ guidelines for safe levels * Routinely test levels in "higher risk" products * Peanuts and peanut butter * Estimated that 4.5 billion people worldwide chronically exposed through diet

Answer 66

* **Found in water, soil, and air** * **Human exposure most common via cigarette smoke & contaminated food/water** * Routinely tested for in public water supplies * Groundwater in West, Midwest, Texas, and Northeast exceed safe limits

Answer 67

**Pathogens that increase the likelihood of cancer.** Produces products that ∆ cell cycle and/or promote chronic inflammation.

Answer 68

* High risk strains ⇒ HPV-16 and HPV-18 * Make proteins that bind pRb, p53, and CKIs (p21, p27) * Linked to CA of cervix, penis, anus, vulva, and vagina

Answer 69

* Virus causes mononucleosis * Have proteins that **function as oncogenes** * Drive production of host genes including cyclin D * Encodes proteins that **inhibit apoptosis** * Linked to Burkett's lymphoma & other CA's

Answer 70

* **Persistent infection w/ HBV or HCV associated with ↑ risk of liver CA** * Might express proteins w/ direct role in carcinogenesis * Both induce long-term infections ⇒ **chronic inflammation** * ∆ cell death and proliferation * Genetic damage accumulates due to immune-mediated hepatic inflammation & oxidative stress

Answer 71

* Chronic infection linked to peptic ulcers * Induces chronic inflammation * Some genes thought to play a role in carcinogenesis

Answer 72

* **Age** * Most important risk factor * _Accumulation of somatic mutations_ * _↓ immune function_ * **Lifestyle choices** * Dietary habits, tobacco/alcohol use, degree of physical activity, sexual and reproductive hx * ⅓ of all cancer deaths due to 5 leading behavioral and dietary risks * **High BMI, low fruit and vegetable intake, lack of physical activity, tobacco use, alcohol use** * **Microbiota** * **∆ homeostasis and immnunostasis** * Upregulation of microbial components (dysbiosis) ⇒ impairment of gut barrier function ⇒ ↑ inflammation * Some bacteria can secrete substances that lead to DNA damage * Hydrogen sulfide, genotoxins, ROS * Can induce inflammatory responses ⇒ excessive ROS and NO production by immune cells * **Infectious or inflammatory conditions** * **Immunodeficiencies** * **Certain medications**

Answer 73

Rapidly dividing cells rely on glycolysis for energetic needs and anabolic products. (Even when O₂ plentiful)

Answer 74

_Derived from products of glycolysis:_ * **NADPH** * Electron donor in anabolic pathways * **Ribose-5-phosphate** * For nucleotide synthesis * Derived from PPP * **DHAP** * Lipid synthesis for new membranes * **3-phosphoglycerate** * Precursor for synthesis of serine & glycine * Serine needed for entry of THF into carbon pool * **THF & glycine** * Required for purine synthesis

Answer 75

**Major nutrient sensor of the cell.** * Stimulated by nutrient rich environments * **Coordinates signals for anabolic cell growth and proliferation** * _Upregulates transcription factors_ * **c-Myc** * **HIF-1α** (hypoxia-inducible factor 1 alpha) * ∆ transcriptome of the cell * Leads to reprogramming of glycolysis * ↑ flux by 200x

Answer 76

Relys on glycolysis for ATP and anabolic products. **Triggered by mTOR ⇒ c-Myc and HIF-1α:** * **↑ glucose uptake and trapping** * **⊕ GLUT-3** * Highest affinity / Lowest K_m for glucose * **⊕ Hexokinase (HK-2)** * Highest affinity / Lowest K_m for glucose * Embryonic isoform * **∆ flux through glycolysis** * **⊕ Pyruvate kinase (PKM2)** * Embryonic isoform * Rate of catalysis controls flux * Dynamically regulated between fast tetrameric form and slow dimeric form * **⊕ Pyruvate dehydrogenase kinase** * Inhibits PDH complex * Diverts pyruvate away from TCA * Converted to lactate for ATP

Answer 77

Embryonic pyruvate kinase (PKM2) induced by mTOR. * **Fast tetrametric form** * Favored in the presence of: * Fructose-1,6-bisphosphate * Serine * Intermediates from purine synthetic pathway * Substrates indicates that anabolic substrates are plentiful * **Glycolysis runs at full speed** * **Slow dimeric form** * **Favored in the absence of anabolic intermediates** * **Glycolysis backs up** * Pushes glucose-6-P into other pathways: * PPP * Generate NADPH and ribose-5-P * Lipid synthesis * Amino acid synthesis

Answer 78

* **⊕ Pyruvate dehydrogenase kinase ⇒ ⊗ PDH complex** * ↓ Acetyl CoA ⇒ TCA cycle * **⊕ acetyl-CoA synthetase-2** * Catalyzes acetate → acetyl CoA * Compensates for ↓ [Acetyl CoA] from PDH complex * _Acetyl Co-A needed for:_ * **Lipid synthesis** * **As a substrate for TCA cycle** * Used to generate anabolic substraits * Needed to sustain growth of the cell

Answer 79

**Cancer cells are addicted to glutamine.** * **Directly used in purine and pyrimidine synthesis** * **cMyc upregulates glutaminolysis proteins** * Glutamine transporter * Glutaminase * **Glutaminolysis provides:** * Glutamate * Aspartate * CO₂ * Pyruvate * Lactate * Alanine * Citrate * **Serves as anaplerotic substrates for TCA** * **Provide carbon skeletons for biosynthesis**

Answer 80

* Immune system patrols for invading pathogens & cells that turn cancerous * Abnormal cells detected and removed by healthy immmune system * Tumors can stimulate a protective specific, adpative immune response through tumor specific CD8⁺ T-cells * Malignant cells find ways to escape immune surveillance

Answer 81

1. **Weak immunogenicity** of the tumor due to its host origins 2. Rapid growth of the tumor **overwhelms the immune system** 3. **Selective pressures** on tumor cells promotes the development of mechanisms for evading host immune responses

Answer 82

**Antigens that are uniquely expressed by tumor cells but not by normal cells.** Sometimes referred to as **neoantigens**. Hypothetically, any of these Ag could be recognized by the immune system.

Answer 83

**Normal cellular antigens** expressed at _higher levels_ by tumors as compared to normal cells or at _different stages_ of development or differentiation. **CA-125** ⇒ ovarian cancer **PSA** ⇒ prostate cancer

Answer 84

**Protein or other component in the body** that can be _used as a measurable indicator_ to identify a disease state or assess the severity of the disease.

Answer 85

A **biological factor** which can be _quantitatively measured to yield cancer-related patient information_ including: Cancer predisposition Early detection Monitoring cancerous growth Selection of treatment Overall prognosis TAAs and TSAs can be used.

Answer 86

* Recognize tumor antigens presented by class I MHC * If tumor isn't cleared, cells may upregulate CTLA-4 ⇒ downgregulation of CTL response

Answer 87

* Specific for the tumor antigens * Important in initiation of CTL function * Generates IFN-γ and TNF-α ⇒ classically activated macrophages

Answer 88

* **Stimulated by IFN-γ** * **Kill tumor cells via ADCC** * Recognize _phospholipids_ ectopically expressed by malignant cells * Release lysosomal components and cytokines * Can lead to thrombosis in tumor blood vessels * Results in inhibition of tumor growth

Answer 89

* **Formation of tumor specific antibodies** * ⊕ ADCC by NK cells and macrophages * ⊕ complement-mediated tissue damage and inflammation * **Passive Ab administration** * Therapeutic effect shown * Was linked in some cases to tumor progression

Answer 90

* Down-regulation of MHC I by 50% of tumors * **Loss of MHC I ligand** for _inhibitory receptor_ of NK cells ⇒ tumor killing and cytokine production * Can kill tumor cells by **ADCC** * Killing enhanced by **IFN-γ, IL-12, and IL-15**

Answer 91

* **T_H2 Cells** * Produce IL-10 and IL-4 * Leads to alternatively activated macrophages * T_H2 Cells & M2 macrophages ⇒ microenvironment high in **TGF-β** and vascular endothelial growth factor (**VEGF**) * **Downregulates the immune response** * **Promote tumor angiogenesis** * **Effects could contribute to tumor progression**

Answer 92

The unique cellular composition surrounding the tumor. **Pro-tumor** * T_H2 cells and alternatively activated macrophages * Generates an immunosuppresive environment * Stimulation of T_reg cells * Generation of a low level of chronic inflammation **Anti-tumor** * T_H1 cells and classically activated macrophages * CTLs * B-cells * NK cells

Answer 93

* **Derived from host cells** * Do not express PAMPs * ↓ anti-tumor innate immune response * ↓ adaptive immune response * High mitotic index & genome instability ⇒ **high rates of heritable somatic changes** * Mutations that ↓ tumor immunogenicity have a selective advantage * **Antigenic modulation** * **Low levels of MHC Class I expression** * **↓ expression of adhesion molecules** * **Proteolytic shedding of MIC** * **MIC molecules** ⇒ stress-induced "alterer" molecules * _Binds NK cell activating receptor (NKG2D)_ * NK cells fail to get stimulatory signal * Lack of MHC class I will no longer trigger killing * **Blocking antibodies** * Anti-tumor Ab bound to tumor antigens * ⊗ CTL function * ⊗ ADCC by NK cells

Answer 94

_Tolerogenic state can be induced by:_ * **Failure to induce a robust "danger signal"** * "Danger signal" ⇒ ↑ B7 and MHC class I & II expression * Allows effective stimulation and activation of naive T-cells * T-cell activation in the absence of a "danger signal" is likely to result in **tumor specific T-reg cells** * If naive T-cells encounter tumor Ag without co-stimulation ⇒ **anergy** (peripheral tolerance) * **Poor innate immune response** * **Prolonged antigenic exposure** * If tumor cells are not promptly eliminated ⇒ downregulation of tumor specific T-cells by **AICD** and **CTLA-4**

Answer 95

**Programmed cell death caused by the interaction of Fas:FasL** * Negative regulator of activated T lymphocytes * Results from repeated stimulation of TCR * Helps to maintain peripheral immune tolerance * Both activated T cells and B cells express Fas and undergo clonal deletion by the AICD mechanism * Activated T cells that express both Fas and FasL may be killed by themselves or by each other

Answer 96

T**umors can express or secrete factors that alter the immune response.** * **Inhibitory cytokines** * **TGF-β and/or IL-10** produced by many tumors * Combo ⊗ immune response * ↑ alternatively activated macrophage function * ↑ angiogenesis * **FasL expressed by some tumors** * Binds to **Fas** on leukocytes recruited to the tumor * Causes death of the attacking cells * **Programmed Cell Death-ligand-1 (PD-L1)** expressed by tumor cells * Binds to the PD-1 on activated T cells, B cells, and myeloid cells * Binds to B7 on APCs * Both **PD-L1:PD-1** and **PD-L1:B7** delivers an inhibitory signal to the immune cell * Fosters the development of Treg cells * Blocking this interaction is a major pharmaceutical target

Answer 97

* **Classic anatomical sites protected from immune surveillance** * CNS * Anterior chamber of the eye * Testis * Placenta and fetus * Usually maintained behind a barrier * Barrier either: * **Inhibits the movement of immune** **cells** * Express **cell surface glycocalyx** **molecules** that _hide/cover tumor antigens_ * **Acquired immunoprivileged sites** * Healthy tissues may act as de facto privileged sites because they lack pro-inflammatory or 'danger' signals

Answer 98

Uses **monoclonal antibodies (mAb**) to tumor surface antigens. * **Naked mAb** * **Rituximab (Rituxan)** ⇒ mouse/human chimeric mAb * Binds CD20 on B-cell non-Hodgkin's lymphoma * **Herceptin** **⇒** humanized mAb * Binds HER2/neu * **Ipilimumab (Yervoy) ⇒** fully human mAb * Binds to CTLA-4 * **Conjugated mAb** * Targets a drug, toxin, or radioactive substance directly to the cancer cells * Allows [drug] to be high @ site of malignancy while sparing the rest of the body * mAbs that target tumors can be labeled with radionuclides that emit gamma rays or nanodots to detect tumors and metastatic disease

Answer 99

* Remove tumor cells * Transfect cells with one or more cytokines * IFN-α, IFN-γ, TNF-α, IL-2, IL-12, GM-CSF * Return modified cells to the patient * **Hopes of stimulating a targeted immune response against the tumor**

Answer 100

* **Vaccines** given to patients _who already have cancer_ in the hopes of using **Ag from the tumor to mobilize the immune response against the malignant cells** * Technique involves: * Removal of dendritic cells from the patient * Pulsing the cells with tumor lysates or peptides * Reinfusing cells back into the patient

Answer 101

* **Vaccines that protect from known oncogenic viruses** * ↓ incidence of cancers * ↓ morbidity and mortality * Ex. HPV and Hep B vaccines

Answer 102

Cytotoxic T lymphocyte antigen-4 (CTLA-4) / B7 Pathway * During normal T-cell activation, TCR recognizes Ab bound to MHC class II on APC * Pathway requires a second signal often provided by CD28:B7 * Results in activation and clonal proliferation of the T-cell * **After several days of proliferation, CTLA-4 is up-regulated on the surface of T-cells** * CTLA-4 has a higher affinity for B7 than CD28 * Interaction of CTLA-4 and B7 inhibits the activation response * **CTLA-4 blocks T cells from attacking tumor cells** * **Ipilimumab** ⇒ mAb that targets CTLA-4 * Disrupts its interaction with B7 * **Allows T-cells to attack tumor cells**

Answer 103

* **Normally** * PD-1 functions as an immune checkpoint * Prevents activation of T-cells * Reduces autoimmunity and promotes self-tolerance * PD-1 expressed on activated T cells, B cells, NK cells, and Mφ * Interacts with either PD-L1 or PD-L2 * Tightly controlled through the microenvironment and cytokines * **Some cancers overexpress PD-L1** * Could prompt CTL exhaustion * Down regulation of the immune response * Induction of Treg cells * Overexpression of PD-1 on tumor-infiltrating lymphocytes correlates with poor outcomes * **New drugs target PD-1** * Can activate the immune system to attack tumor cells * Ex. **Opdivo**

Answer 104

* Treatment options: * **Selective T_reg inhibitors** * **TGF-inhibiting mAb** * Drugs are being explored to see if they can selectively deplete T_reg cells without impacting other T-cell subclasses * Allows a more anti-tumor response

Answer 105

* **Tansfusion of T-cells into a patient** * Has been tested for treatment of cancer and chronic infections * Currently in various stages of clinical trials

Answer 106

Treatment for certain relapsed or refractory leukemias: * Infusion of **alloreactive T cells** following complete or partial **hematopoietic stem cell transplant** * **Non-host T-cells attack non-donor targets including host tissue** * Often causes graft-vs-host reactions * Goal for alloreactive donor T-cells to respond against residual tumor cells * Contributes to eradication of the tumor or graft-vs-tumor response

Answer 107

* Engineered receptors * **Single polypeptide ligand binding domain** grafted onto a T-cell signaling domain * _Chimeric molecule_: * **Antibody-derived recognition moiety** * **CD3-Zeta (activation domain)** * **Costimulatory domain** * CARs then integrated into a retroviral vector * **Patient T-cells are harvested and transformed ex vivo** * T-cells transferred back into the patient * CAR T therapy currently used to treat acute lymphoblastic leukemia (ALL) by targeting CD19 * Marker of both normal and neoplastic B cells

Answer 108

1. **Suppresion of viral infections** * Infection can induce certain kinds of tumors 2. **Timely elimination of pathogens to reduce extent and duration of inflammation** * Chronic inflammation can promote tumorigenesis 3. **Immunosurveillence** * Identifies and destroys transformed cells before they can establish malignancy

Answer 109

* Selective pressures and genome instability promote **decreased immunogenicity** * Antigenic modulation * Low levels of MHC class I expression * Decreased expression of adhesion molecules * Proteolytic shedding of MIC * Blocking antibodies * Tumors can arise in healthy tissues without a “danger signal” ⇒ **antigens often viewed as self** * Tumors induce **immune suppression** * Tumors can **arise in immunoprivileged sites or sites with decreased immunosurveillance** such as adipose tissue and the CNS

Answer 110

* Localized overgrowth of tissue * No infiltration or metastasis * Neoplastic cells closely resemble orgin tissue ⇒ well-differentiated

Answer 111

**Tissue architecture resembles adjacent normal tissue.** Parenchyma or stromal cells are usually not prominent.

Answer 112

**Suffix "oma" preceded by tissue of origin** * _Mesenchymal origin_ ⇒ CT and derivatives * **Fibroma** ⇒ composed of fibroblasts and collagen matrix * **Lipoma** ⇒ composed of adipocytes and little stroma * Usually surrounded by a fibrous capsule * **Chondroma** ⇒ composed of chondrocytes * Also refers to benign tumor of the bone * _Epithelial origin_ * **Papilloma** ⇒ contain finger-like projections of epithelial structures * **Adenoma** ⇒ forms glands * **Cystadenoma** ⇒ forms cyts in a glandular background * _Muscle origin_ * **Leiomyoma** ⇒ made of smooth muscle

Answer 113

**Benign tumor composed of disorganized tissue.** * Formed by cells that belong in that tissue but are not arranged properly * Ex. Hamartoma in the lung * Composed of cartilage, respiratory epithelium, smooth muscle, and mucus glands * Mishapen lump of tissue

Answer 114

**"Heterotropic rest"** * **Nest of normal cells from a different tissue** * Ex. pancreatic tissue in stomach

Answer 115

Benign tumor made of cells that come from different germ cell layers.

Answer 116

_Dependent on many factors:_ * **Rate of cell division vs rate of cell death** * **Growth rate generally inversely related to degree of cellular differentiation** * _Highly differentiated cells_ ⇒ slower growth rate * _Undifferentiated cells_ ⇒ faster growth rate * Often comprised of **small dark staining cells with little cytoplasm** * High nuclear:cytoplasm ratio

Answer 117

* Malignant cells **infiltrate** into surrounding tissue * **Locally invasive** * Capacity to **metastasize** * Shows **genetic instability** * Neoplastic cells **appear different from tissue of origin** * Normal cellular arragement may be disrupted * Nuclei tend not to be at basal side of epithelium

Answer 118

* **Tissue architecture varies** * _Well or moderately differentiated_ ⇒ retains qualities of origin tissue * _Poorly differentiated_ ⇒ has lost qualities of origin tissues * **Stroma generally reactive** * Local fibroblasts respond to tumor ⇒ **desmoplastic response** * _↑ collagen deposition_ * Fibroblasts can produce **growth factors** * Sustains growth/survival of malignant cells * Can be **scirrhous** * Firm, irregular texture * Gritty

Answer 119

**Suffix "carcinoma" preceded by tissue of origin.** * Tends to sprad to regional lymph nodes first * Can metastasize from there via bloodstream to distant sites

Answer 120

**Suffix "scarcoma" preceded by tissue of origin.** * Usually do not spread to lymph nodes * Goes right to hematogenous route * Look for metastasis in lungs

Answer 121

Do not follow the rules ⇒ end in "oma" * Glioblastoma * Neuroblastoma * Medulloblastoma * Multiple myeloma * Plasmacytoma * Lymphoma * Melanoma * Mesothelioma

Answer 122

**Loss of normal function ⇒ loss of associated morphology** _Common features of malignant cells:_ * **Pleomorphism** ⇒ ↑ variation in shape within population * **Anisocytosis** ⇒ ↑ variation in size within population * **↓ cell-cell adhesion** * **Loss of polarity** * Sheets or masses of cells grow in a disorganized fashion * **Mitoses** * Can be atypical * Contain abnormal mitotic figures * Tripolar, quadripolar, or multipolar spindles

Answer 123

**Based on the degree of differentiation of the cells within a tumor.** * Well-differentiated ⇒ **low grade** * Ex. squamous cell carcinoma that makes keratin * Retains its "squamous-ness" * Poorly-differentiated ⇒ **high grade** * Ex. Squamous cell carcinoma that does not make keratin * Often correlates with more aggressive tumor behavior * Completely undifferentiated ⇒ **anaplastic** * Sign of a highly malignant tumor

Answer 124

**Based on the extent of invasion/metastasis.** **_TNM system:_** * **T** ⇒ **_T_**umor characteristics * Size * Depth of invation into normal tissue * **N** ⇒ Number of lymph **_n_**odes involved * **M** ⇒ **_M_**etastasis * Presence of metastasis ⇒ M1 * Absence of metastasis ⇒ M0 Any tumor that _demonstrates distant metastasis_ is considered **Stage IV cancer** regardless of T and N values.

Answer 125

**Based on the clinical severity of the disease.** - Extent of tumor - Spread

Answer 126

* **Benign tumor** * Well-circumscribed, smooth interface between tumor and surrounding breast tissue * Glands distinguishable ⇒ adenoma * Embedded in stroma of fibroblasts and collagen ⇒ fibroma * Tumor known as a **fibroadenoma** * **Malignant tumor** * Poorly circumscribed * Has irregular extensions into surrounding breast tissue * Cells resemble glands but lack organization of normal mammary tissue * Tumor called an invasive **adenocarcinoma**

Answer 127

Distinct changes that occur in tissues prior to the appearance of a malignant tumor.

Answer 128

_Progression within an epithelial layer towards malignancy:_ * **Metaplasia** * A change in the epithelial layer to another epithelial cell type * **Dysplasia** * Disorganization within the epithelial layer * **Carcinoma in situ** * Clearly malignant cells are present in the epithelial layer * No malignant cells observed below the basement membrane * **Invasive carcinoma** * Cells invade the submucosa and spread into into the surrounding tissue * If left unchecked, malignant cells will invade further into the lymphatics and circulatory system * Forms metastatic lesions of tumor in distant tissues

Answer 129

Areas of **abnormal tissue organization and higher frequencies of mitotic figures** within a normal epithelial layer. * Ex. adenomatous polyp of the colon * Cells lose normal appearance * Dysplastic nucleus elongated and no longer sits on basement membrane * Appears stratified * Mucus vacuole may not be seen

Answer 130

* Malignant cells invade local tissue * If epithelial cells, **must acquire ability to migrate through the basement membrane** * Requires production of new proteins * Proteases to degrade tissue matrix * Survival factors to allow survival outside of origin tissue

Answer 131

_3 main routes for spread beyond local barriers:_ 1. **Direct seeding of body cavities** * Tumor cells must have access to the area * Ex. ovarian carcinoma often seed the peritoneum once they have spread beyond the ovary 2. **Lymphatic spread** * Most common path for carcinomas * Follows normal lymphatic drainage for origin tissue * Lymphadenopathy may be due to metastasis or a reactive immune reaction in response to tumor growth 3. **Hematogenous spread** * Most common route for sarcomas * Venous more common than arterial spread Within the blood or lymph, **tumor cells must be able to survive without integrin attachment**.

Answer 132

* **Local impingement of tissues/structures** * Ex. glioblastomas in the brain * **Pain** * **Compression** * **Bone fractures** * **Tumor cachexia** * Caused by cytokines ⇒ TNF-α, IL-1, IFN-𝛾 * **Hormone effects** * Produce effects not directly due to the physical tumor * Ex. hyponatremia 2/2 lung cancer secreting substance similar to ADH * Called a paraneoplastic syndrome

Answer 133

Secretion of hormones by tumors.

Answer 134

**There is a minimum number of cells required for a tumor to be detected.** * Ex. 1-gram tumor contains 1x10⁹ cells * Assume clonality ⇒ arose from a single cell * Takes 30 generations to reach 1x10⁹ cells * Could reach 1 kg size in 10 more doublings

Answer 135

* Important tool for tumor evaluation and diagnosis * Ideally: * Tumor marker detectable even when tumor is very small * Action can be take before tumor becomes clinically significant * Hopefully before it is capable of metastasis

Answer 136

* **Protease secreted by the prostate** * Cleaves binding protein for insulin-like growth factor * **↑ [PSA] with prostate cancer or hyperplasia** * **Biomarker for prostate cancer** ⇒ a tumor associated antigen (TAA) * Useful to monitor cancer recurrence s/p prostatectomy * Lack of specificity ⇒ limited clinical impact * Could lead to un-needed interventions or anxiety

Answer 137

**Tumor markers used to help ID origin of malignant cells.** * _Ex. Patient w/ hx of prostate CA has new liver masses_ * Multiple masses more suggestive of metastasis * Mass removed via biopsy & sent to pathologist for evaluation * **Stain tissue sections with Ab for various tumor Ag** * PSA ⇒ prostate CA * CA19-9 ⇒ pancreatic CA * CEA ⇒ colon CA * If Ab to PSA stains tumor cells ⇒ dx with metastatic prostatic adenocarcinoma in the liver