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Flashcards in Infectious Causes of Cancer Deck (68):
1

Carcinogenesis background?

1. non lethal genetic damage

2. regulatory genes

-oncogenes

-tumor suppressor genes

3. genes regulating cell death (apoptosis)

4. DNA repair genes

2

Steps leading to malignant neoplasm? (3)

chart

3

Protooncogenes vs oncogenes?

-proto- normal

-oncogenes- same gene but abnormal

-1000s of oncogenes are known

-only need one of two alleles for protooncogenes to become oncogenes

-autosomal dominant expression, mutated allele takes over

4

Actions of oncogenes? (5)

pic

5

Growth factors mutations?

1. mutations in genes encoding growth factors

-growth factor could be involved with turning on cell activity

-increased growth factor production alone is not sufficient for neoplastic transformation

-c sis encodes B chain of PDGF

-astrocytomas and osteosarcomas produce PDGF

-same tumors express receptors for PDGF autocrine stimulation

6

Growth factor receptor mutations?

1. several are transmembrane proteins

2. oncogenic versions

-associated with persistent dimerization and activation without binding to growth factors

-result- constant mitogenic signaling

-higher abundance- amplification of protein, too much

-normal growth factors will bind to all receptors of same cell, leads to over activation

7

Mechanisms of growth factor receptor activation in human tumors?

1. most common is over expression of receptors

-gene amplification

-3 members of EGF receptor family commonly involved

8

Normal growth factor vs abnormal, over expression? (9,10)

pics

-stimulate angiogenesis

9

Inhibiting drugs of over expression of receptor? (11)

-binds receptor to prevent growth factor from binding it

10

Signal transduction proteins mutations? (14)

1. Ras family of guanine triphosphate (GTP) binding proteins

-10 to 20% of all humans tumors are mutant Ras

-mutation of Ras gene is the single most common abnormality of dominant oncogenes in human tumors

-in inactive state, Ras binds GDP, upon growth factor stimulation, Ras is activated by exchanging GDP with GTP

2. activated Ras excites MAP kinase path, binds to Raf1

-excited MAP kinases activate nuclear transcription factors, initiate mitogenic response

3. GAPs bind Ras, increase GTPase activity of Ras 1000 fold

-mutant Ras- GAPs still bind but no increased GTPase activity

4. Ras also has some control on level of cyclin dependent kinases to effect cell cycle regulation directly

11

process of Ras stimulation normal? (14)

1. growth factor activates growth factor receptor to activate signal transduction process

2. through bridging protein, inactive Ras protein is stimulated, farnesyl membrane anchors protein to membrane

-has GDP bound

3. inactive Ras drops its GDP and becomes bound to GTP

4. Ras is now active

5. binds to Raf1 and GAP proteins to help active Ras become more active

-activity level is 1000 fold more

-needs to cleave GTP, signals to cell to undergo signal transduction to signal other proteins to activate transcription factors in nucleus

12

Process of Ras stimulation abnormal? (14)

1. active Ras is bound by GTP but stays bound to it

2. it stays activated to continue sending signal to cell for transcription in nucleus

 

1. Gap proteins can be abnormal, cannot increase activity of Ras and stays on

2. GAP is made by tumor suppressor gene, controls ability of Ras to cleave phosphate group off GTP

-Ras is oncoprotein from oncogene

13

Nuclear transcription proteins?

1. many oncoprotein have been localized to nucleus (myc, myb, jun, fos)

2. myc gene is most commonly involved in human tumors

3. normally an early response gene induced when cells are signaled to divide

14

Cyclins and cyclin dependent kinases? (17)

1. mutations of genes encoding these are found in several human cancers

2. cyclin D and CDK4 (CDK6) are over expressed in many cancers, more so than any other cyclins

3. cyclins bind with kinases and become phosphorylated

15

CDKs? (18)

1. phosphorylation event for retinoblastoma protein

-poorly hypophosphorylated, its active, it is bound to other proteins

2. when phosphorylated it is inactivated

-releases other proteins

3. activate DNA pol, hydrofolate reductase, other enzymes involved with DNA synthesis

4. S phase, G2 phase, mitosis occurs

5. genome is now replicated, divided, now new cell is created

6. this process is ongoing

-CDKs are growth promoting so they are oncogenes

-retinoblastoma keeps brake on system so it is a tumor suppressor protein

16

Tumor suppressor genes?

1. brakes to cell proliferation

2. 30 tumor suppressor are known

17

Protein products of tumor suppressor genes?

1. genes encoding components of growth inhibiting paths

2. these paths involved cell proteins at the level of nucleus, cytosol, plasma membrane, and cell surface

18

Known tumor suppressor genes? (21)

chart

19

tumor suppressor genes involved in nuclear transcription and cell cycle?

1. Rb gene

2. p53 gene

3. BRCA-1 and BRCA-2

20

Rb gene?

1. first tumor suppressor gene discovered

2. pRB is a nuclear protein, plays a key role in cell cycle, active state is underphosphorylated

3. active state, brake from G1 to S

4. phosphorylation inactivates pRb

5. S phase will ensue, during M pRb is again dephosphorylated

6. in hypophosphorylated form, pRb binds to E2F transcription factor, together bind to DNA to inhibit S phase genes

7. upon deletion or mutation, E2F is released, binds to E2F responsive genes, cell cycle is activated

21

Functions of p53?

wild type:

-cell differentiation

-cell cycle arrest in G1

-inhibit DNA replication, helicase activity, Rb phosphorylation

-represses transcription of murine double minute (Mdm2 oncogenes)- Mdm2 normally inactivates wild type p53, acts as oncogene

-apoptosis in response to x irradiation and chemotherapy

22

p21 (Waf1/Cip1)?

-cyclin dependent kinase inhibitor of G1

-p21 gene induced by p53 in response to DNA damage

23

BRCA 1 and 2?

1. associated with breast cancer, ovarian, colon, prostate cancers

2. inherited germ line mutations increases susceptibility to breast cancer

-with germ line mutation, greater susceptibility also to epithelial ovarian cancer

3. 5-10% of breast cancer is familial, 80% due to mutations of these two genes

-mutations of these two genes are rarely found in sporadic breast cancer

4. functions normally for DNA repair, code for proteins that bind RAD51 gene

-RAD51 is DNA repair protein, surrounds abnormal DNA to try to fix it

-if abnormal BRCA, RAD cannot fix problem of DNA

24

Genes that regulate signal transduction?

1. APC

2. NF-1

25

NF-1 tumor suppressor gene?

1. NF-1 (neurofibromin protein) regulates Ras

-acts as a GTPase activating protein (GAP), facilitates conversion of active Ras to inactive Ras

-loss of NF-1, Ras stays active, continual signal transduction

26

Adenomatous Polyposis Coli (APC) gene?

1. germ line mutation of APC, associated with benign tumors

-these are precursors of carcinomas that develop later

-individuals with one mutant allele, numerous polyps found in colon in teens and twenties, overgrowth of epithelial cells

-both copies of gene must be mutated to get tumor development, first tumors are adenomas, more mutations are required to get carcinomas

-70-80% of non familial colorectal carcinomas and sporadic adenomas have homozygous loss of APC

2. APC gene codes for APC protein which binds beta catenin (factors in cell involved with cadherin proteins stay bound together and cell to cell interaction) mutated APC lets beta catenin get released from cytoplasm into nucleus to turn on cell cycle

27

Cell surface receptors?

1. TGF beta suppresses MYC gene transcription

2. pRb mediates actions of TGF beta, intermediary for MYC transcription

-if pRb is mutated or lost, no TGF beta suppression

28

Genes regulating apoptosis?

1. bcl2, bcl-xl- anti apoptotic

2. bax, bad, bid, bcl-xS- pro apoptotic

29

DNA repair genes?

-hMSH2

-hMLH1

-hPMS1

-hPMS2

30

DNA micro satellites?

1. repetitive triplet repeats of nucleotides

2. instability represents larger repeats related to deficient DNA mismatch repair genes, these genes act as spell checkers

-hMSH2, hMLH1, hPMS1, hPMS2

31

Cancers associated with defective repair of DNA?

1. Xeroderma pigmentosum

-increased risk of skin cancer with UV exposure

-cross links pyrimidines, prevents DNA replication

-defect in NER

2. HNPCC (lynch syndrome)

-at least 4 mismatch repair genes involved

-colon cancers (cecum and proximal colon cancer occur at younger ages)

-2-4% of all colon cancers

32

Molecular events of oncogenesis summary?

1. amplified oncogene expression

2. loss of heterozygosity (homozygous deletion) or mutation of tumor suppressor genes or change in gene expression levels

3. impaired DNA repair and micro satellite instability

33

General considerations of oncogenes and tumor suppressor genes? (38)

oncogenes

-activation event

-L/L = leukemia/lymphoma

34

Viruses known to cause cancer? (40)

pic

35

four main oncogenic DNA viruses?

1. human papillomavirus (HPV)

2. epstein barr virus (EBV)

3. hep B virus (HBV)

4. kaposi sarcoma virus (KSHV)

36

DNA virus characteristics?

1. transforming viruses

-stable associated with host genome

-viral genes transcribed early in life

-life cycle is important (latency)

-some reside in cells and not cause cancer

37

Process of virus attaching to cell and causing cancer? (43)

pic

38

Human papillomavirus (HPV)?

1. papovavirus family

-naked icosahedral DNA virus

-100 different types

2. transmission

-breaks in skin

-sexually transmitted

-birth canal

3. squamous cell carcinoma- cervical, oral/laryngeal

4. STD leading to cervical carcinoma

-may also find chlamydia trachoma's as another risk factor

39

Prevalence of HPV?

1. benign warts (multiple serotypes)

-most common manifestation of HPV infection

-children and young adults

2. genital warts (HPV types 6 and 11)

-one of the fastest growing sexually transmitted disease in the US

-6.2 million new cases of HPV in US per year

40

Prevalence of genital HPV?

-estimated that 80% of sexually active women have acquired HPV by age 50

-20 million people in US have genital HPV

-numbers are estimates because HPV infection is not reported (only cervical cancer reported)

-genital HPV incidence in women less than 25 (28-40%)

-50-75% of infections are high risk subtypes:

-HPV 16 and 18- 85% of cervical shamus cell carcinomas, dysplasia and carcinoma in situ

-HPV 31, 33, 45, 52, 58 (part of Gardasil 9 vaccine)

-high grade cervical dysplasia more common in women over 35

-over 99% of cervical cancers have HPV DNA detected within tumor

41

What does HPV do?

1. integration of DNA into host genome causes transformation

2. viral DNA always disrupted at same site (the E1/E2 open reading frame)

-E2 usually represses early genes E6 and E7 of virus

3. E1/E2 split causes over expression of E6 and E7 proteins of HPV16 and 18

4. oncogenic potential due to E6 and E7

-E6 binds p53 tumor suppressor protein- results in degradation

-E7 binds to pRb tumor suppressor protein- results in unbinding of E2F transcription factor

42

HPV infection process, p53? (50)

pic

43

HPV infection process, pRb? (51)

pic

44

What does HPV initiate?

1. initiator of transforming events- requires somatic mutations

-cofactors such as smoking, other infections, nutritional deficits, hormones

-probably not acting separate from environmental factors

45

Herpes virus?

1. dsDNA, enveloped

2. potential for latency and reactivation, immortalization and transformation

3. tegument- space between envelope and capsid

-contains viral proteins, possible mRNA, that help initiate viral replication

46

Classification of herpes?

1. subfamilies

-alpha, beta, gamma

2. criteria:

-organiziation of genome

-tissue tropism and site of latency

-pathogenesis and disease manifestation

47

Alpha herpes virus types?

1. herpes simplex virus type 1 (HSV-1)

-official name HHV-1

-cold sores

2. herpes simplex virus type 2 (HSV-2)

-official name HHV-2

-genital herpes

3. varicella zoster (VZV)

-official name HHV-3

-chicken pox, shingles

48

Beta herpes virus?

1. cytomegalovirus (CMV)

-HHV-5

-most serious for children

2. human herpes virus 6 (HHV-6)

3. human herpes virus 7 (HHV-7)

49

Gamma herpes virus?

1. Kaposi's sarcoma herpesvirus (KSHV)

-HHV-8

2. epstein barr virus (EBV)

-HHV-4

50

Productive and latent infections? (58)

-a lot of them are harbored by WBCs

51

serological markers of productive infections?

1. early antigen (EA)

2. viral capsid antigen (VCA)

3. membrane antigen (MA)

52

Epstein Barr virus (EBV-HHV4) 4 types of cancers?

4 types:

1. burrkits lymphoma

2. B cell lymphoma in immunosuppression

3. hodgkins disease

4. nasopharyngeal carcinoma

53

EBV prevalence?

-US over 70% of population is infected by age of 30

-industrialized nations approx 50% of infections delayed until adolescence or young adulthood

-12% of susceptible college age students seroconvert each year, 50% come down with mononucleosis

54

EBV transmission?

-contact with contaminated saliva

-reactivation is asymptomatic

-viral shedding occurs (person is infectious)

55

EBV cell tropism?

1. cell tropism determine by presence of EBV receptor

2. binds CR2 and CD21 (receptor for C3b, component of complement) on B cells and epithelial cells of the oropharynx and nasopharynx

-MHC II molecules are used as coreceptors

3. linear genome forms circular episome in nucleus, latent infection (no viral replication and no cell death)

4. B cells- immortalized and propagate

56

EBV genes?

1. some immediate early genes are expressed

-EB nuclear antigens (EBNAs)

-latent proteins (LP)

-latent membrane proteins (LMP)

-2 small epstein barr encoded RNA molecules (EBER)

57

EBV viral proteins?

1. viral proteins lead to dysregulation

2. LMP1 antiapoptotic- binds bcl-2 and activates growth promoting pathways

-shuts down ability of bcl-2 to be pro apoptotic

3. LMP1 in rodent lines- leads to tumors

4. LMP1 in transgenic lines (in skin results in hyperplasia and abnormal keratin)

58

Other transforming potential of EBV?

-EBV encoded EBNA2 gene that transactivates host genes such as cyclin D and src and even activates the viral LMP1 gene (its own material)

-translocation (8:14) results in c-myc activation:

-on chromosome 8 has myc gene, 14 has IgG heavy chain gene

-myc gene gets translocated next to IgG gene, they both get turned on, increased myc activity and increased proliferation of B cells making antibody

-B cell lymphoma

59

Immortalization of B cells by EBV?

1. cells are stimulated to divide and secrete antibody

-polyclonal activation

-heterophile antibodies

-IgM which recognizes antigens on sheep, horse, bovine, RBCs

-called hetero because IgM antibodies will recognize red cells from other species

2. EBV activated B cells are eliminated by T cells

-activation and proliferation of T cells produces mononucleosis

-lack of T cell control may result in a lymphoma

60

Reactivation of EBV?

-virus latently infects memory B cells, reactivates if the cell is activated

-common in tonsils and oropharynx

-virus is shed in saliva -reactivation is asymptomatic

61

Kaposi Sarcoma Herpesvirus (HHV8)?

-discovered in 1994- genome found in all KS lesions including HIV negative individuals

-50% of B cells in pts with KS have KSHV -sexually transmitted

-infects B cells, vascular endothelial cells, perivascular spindle cells and others

62

HHV8 (kaposi) clinical infections?

1. Kaposi sarcoma (AIDS defining illness)

-spindle cells- derived from endothelial cells

-KSHV sequences associated with KS at all stages of tumor formation

-KSHV sequences associated with both AIDS related and non related AIDS KS

-17% of HIV/KSHV co infected patients will develop KS

-virus expresses proteins with homology to cell proteins (our proteins) that promote growth and inhibit apoptosis

2. encodes homologs of human proteins important for cell proliferation

-IL6 (mitogen for spindle cells in lesions)

-bcl2 (anti apoptotic proteins)

-cyclin D (regulates cell cycle G1-S phase)

-KS cells secrete TNFalpha, IL1, IL6, GMCSF, bFGF

-carcinoma is more epithelial or glandular tissue

3. B cell lymphoma

-KSHV sequences associated with a rare form of AIDS related B cell lymphoma (body cavity based lymphomas)

-lymphomas often co infected with EBV

4. multi centric castle mans disease -lymphoproliferative disease

5. prostate gland

-KSHV sequences associated with abnormal tissue from prostate glands

-infection thought to be latent in glandular epithelial cells of prostate gland

-virus could be shed in prostate secretions

-co factor for a subset of prostate cancer

63

Background of hepatitis viruses?

1. hep viruses A-E

2. HAV and HBV were identified first

-HAV infectious hepatitis

-HBV serum hepatitis

3. NANB hepatitis mostly due to HCV

4. A, B, C are responsible for over 95% of cases of acute hepatitis

5. B, C, D can cause chronic, A and E can cause acute

64

Hepatitis B virus?

1. HBV and liver cancer (hepatocellular carcinoma)

-endemic in far east and africa

2. integrated into host genome- tumors are clonal

-no oncoprotein is coded, no insertion near known protooncogenes

3. encodes a regulatory protein called Hbx

-it disrupts growth control- activates insulin like growth factor II gene and receptors for this

-binds p53- inhibits apoptosis

65

Transmission of HBV?

1. high viral titers in blood

-moderately high titers in semen and vaginal fluid, low or none in urine, feces, or breastmilk

2. blood transfusions

-no longer a common source of transmission (blood screening)

3. IV drug use and sexual transmission more common now

-male homosexuals or people with multiple sex partners

4. HBV can be transmitted vertically (mother to child)

66

Hepatitis B surface antigen (HBsAG)?

1. surface glycoprotein (HBsAG)

-3 initiation codons (small, medium, and large HBsAG)

-dane particles (infectious form) has mostly small HBsAG and 30% medium and large HBsAG

-small spheres and filaments- different ratios of small, medium, large form of HBsAG

2. anti HBsAG clears virus and protects against re infection

67

Helicobacter pylori and other bacteria?

1. marshall 1984- showed H. pylori causes most peptic ulcers

2. now implicated in B cell lymphoma of the stomach (MALT) and stomach carcinoma

3. chlamydia pneumoniae- lung, carcinoma, CTCL?

4. chlamydia trachomatis- STD, cervical carcinoma?

-lives in mucus

-most of us have it, but only affected if gets in stomach

68

miRNAs and cancer?

1. small RNA molecules that regulate gene expression post transcriptionally

2. malignant tumors and tumor cell lines have widespread deregulated miRNA expression compared to normal tissues

3. abundant class of RNAs in plants, animals, and DNA viruses

4. many miRNA genes are located at fragile sites in the genome, regions that are commonly amplified or deleted in human cancer