Unit 2: Molecular Basis of Cancer

causes of non-lethal damage to DNA

- radiation

- chemical

- UV exposure

- virus

- food

- spontaneous mutation

clonal expansion

- tumors are formed by clonal expansion of one original mutated cell

principle targets of DNA damage

- proto-oncogenes

- tumor suppressor genes

- regulation of cell death

- regulation of DNA repair

proto-oncogenes

- genes involved in normal cell growth promotion

- mutations in a proto-oncogene may cause it to become 'active' when it is not supposed to be

- malfunctioning proto-oncogene is called an oncogene, which can cause the growth of cancer cells

regulation of cell death

- apoptosis is a normal and controlled part of an organism's growth and development

- in adults, used to rid the body of cells that have been damaged beyond repair

regulation of DNA repair

- genome integrity is challenged by DNA damage which must be repaired to allow to accurately read and duplicate the information in the genome

- multiple repair enzymes scan the DNA for problems, remove the offending damage, and restore DNA complex

proto-oncogenes promote ...

- signaling pathways that control the cell cycle, cell differentiation, DNA repair

- help maintain balance of cell growth and prevent uncontrolled cell proliferation

mutated proto-oncogenes

- become oncogenes

- can promote excessive cell division leading to cancer

- lose regulatory function and become drivers of tumorigenesis

proto-oncogenes include ...

- growth factors

- growth factor receptors

- signal transduction proteins

- nuclear regulatory proteins/transcription factors

growth factors

- induce proliferation

- after mutation, can switch from paracrine action to autocrine action

- increased proliferation

glioblastoma

- platelet derived growth factor (PDGF) suggested to be the driver for development of glioblastoma

- glioblastomas overproduce PDGF

growth factor receptor

- oncogenic GFRs constitutively dimerize and are over expressed

- can activate signal without ligand after dimerization

ERBB1 gene

- oncogenic epidermal GFR

- 80% of squamous cell carcinomas of lung

ERBB2 gene

- oncogenic epidermal GFR

- also called HER2/neu gene

- 25-30% of breast cancers

- leads to more aggressive disease, increased recurrence, worse prognosis, decreased survival

ERBB2 gene / HER2/neu mutation treatment

- trastuzumab (Herceptin)

- mAB to Her2/neu

- example of targeted immunotherapy

- blocks HER2 receptors and can alert immune system to destroy cancer cells

RAS

- oncogene for signal transduction

- normal RAS plays a role in GF mediated signal transduction for mitogenesis and cell proliferation

- normally binds and hydrolyzes GTP

- mutated RAS gets stuck in active form

RAS mutation prevalence

- 15-20% of human tumors have a mutated form of RAS

- especially human carcinomas

mutation of RAS causes deregulation of ...

- proliferation

- differentiation

- cell adhesion

- apoptosis

- cell migration

ABL1

- oncogenic signal transduction protein

- encodes protein tyrosine kinase, which plays a role in differentiation, cell division, cell adhesion

BCR-ABL

- translocation of ABL (9) to BCR (22)

- constitutively active cytoplasmic tyrosine kinase

- around 90% of patients with chronic myeloid leukemia (CML) have this translation

- also called the Philadelphia chromosome

treatment for BCR-ABL mutation

- block action of tyrosine kinase

- imatinimab mesylate (Gleevac)

- nilotinimab

- dasatinimab

MYC gene

- nuclear regulatory protein

- binds to DNA and leads to transciption

- expressed in practically all eukaryotic cells

- initiates cell proliferation and high rate of cell division

- immediate early response gene (rapidly induced)

- mutated version is oncogenic

Burkitt's lymphoma cause

- mutation of MYC into oncogene (deregulation of expression, usually due to translocation on chromosome 8 to 14)

- high grade B cell lymphoma

Burkitt's lymphoma prevalence

- rare cancer in US

- most common childhood cancer in Africa (strongly linked to EBV infections)

- immunodeficiency-associated form (seen in patients with HIV infection and post-transplant patients)

contact inhibition

- a process of arresting cell growth when cells come into contact with each other

- normal cells stop proliferating when they form a monolayer in a culture dish

- lost in cancer cells

B catenin

- involved in maintaining cell-cell adhesion and contact inhibition by binding to E-cadherin (part of cell to cell adhesion complex)

- functions as a transcription factor when not attached to E-cadherin

- activated when WNT signaling is activated

loss of E-cadherin

- cancer cells frequently lose E-cadherin

- releases B catenin from adhesion complex, which moves to the nucleus to initate cell proliferation

- B catenin now functioning as a oncogenic transcription factor

- shown in multiple cancers, including breast, colon, ovary, and prostate

tumor suppressor genes

- encode a protein that acts to regulate cell division

- when a tumor suppressor gene is inactivated by mutation, the protein it encodes is not produced or does not function properly

- without correct functioning, uncontrolled cell division may occur

- mutations may contribute to development of cancer

retinoblastoma (RB) gene inheritance

- first tumor suppressor gene discovered

- 25-30% of retinoblastomas inherit mutation for retinoblastoma gene

- both alleles must be mutated to give rise to tumor

- mutations lead to retinoblastoma and other cancers

retinoblastoma function

- role at G1/S checkpoint, provides break

- regulates the binding of E2F to DNA

- hypophosphorylated = active, bound to E2F

- hyperphosphorylated = inactive, cells allowed to divide

- if mutated, gets stuck in inactive form

p53 overview and activation

- guardian of the genome :)

- nuclear transcription factor

- activated by a variety of stresses including DNA damage, oxydative stress/hypoxia, osmotic shock, deregulation of oncogenes

p53 regulation and function

- regulated by MDM2 (when bound to MDM2, inactive)

- when active, can induce growth arrest by holding cell at G1/S

- activates DNA repair

- initates apoptosis or senescence if DNA cannot be repaired

- inhibits angiogenesis

senescence

- state where cell remains metabolically active but stops dividing

p53 mutation prevalence

- large number of tumors contain mutation

- very common in target tumors

- most are sporadic mutations

Lifraumeni syndrome

- inherited mutant p53 allele

- rare disorder

- individuals are 25 fold more likely to have cancer before age 50

- large range of cancers in these patients including sarcomas, breast cancers, leukemias, brain tumors

average replicative potential of a cell

- 60-70 cell doublings

- shortening of telomeres leads cell to stop dividing

telomerase

- not expressed by normal cells

- tumor cells reactivate telomerase (present in more than 90% of cancers)

- if normal cells start to express telomerase, usually p53 is activated to turn cell senescent

pro-apoptotic regulators

- BAX and BAK form pores in mitochrondria membrane inducing apoptosis

- cBAX and BAK can be induced by p53

anti-apoptotic regulators

- BCL-2 and BCL-XL

- inhibit pro-apoptotic regulators

follicular B cell lymphomas

- 85% carry a BCL2 translocation which leads to increased expression of BCL2

- mutatation causes B cells to live longer

- disease progression is indolent (slow)

regulators of DNA repair

1) mismatch repair genes

2) nucleotide excision repair

3) repair by homologous recombination

mismatch repair genes

- spell checkers

- ensure proper pairing

- mutation causing disease example: hereditary non-polyposis colon cancer (HNPCC)

nucleotide excision repair example condition

- xeroderma pigmentosum

homologous recombination example condition

- BRCA 1 and 2 genes causing breast cancer

- homologous recombination repair is the repair of DNA double strand breaks using a homologous strand

multi-step carcinogenesis

- multiple genetic alterations involving both the activation of many oncogenes and loss of more than one tumor suppressor gene are necessary for carcinogenesis