patoloji-ders-notlari

Title

Serdar Balcı

Hallmarks of Cancer-1

Serdar BALCI, MD

Cell. 2000 Jan 7;100(1):57-70.

Cell  2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

Cell. 2011 Mar 4;144(5):646-74

Copyright © 2011 Elsevier Inc. Terms and Conditions

Cell  2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

Cell. 2011 Mar 4;144(5):646-74

Copyright © 2011 Elsevier Inc. Terms and Conditions

Cell. 2000 Jan 7;100(1):57-70.

Cell  2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

Cell. 2011 Mar 4;144(5):646-74

Copyright © 2011 Elsevier Inc. Terms and Conditions

Cell. 2000 Jan 7;100(1):57-70.

Cell  2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

Cell. 2011 Mar 4;144(5):646-74

Copyright © 2011 Elsevier Inc. Terms and Conditions

Cell. 2000 Jan 7;100(1):57-70.

Cell  2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

Cell. 2011 Mar 4;144(5):646-74

Copyright © 2011 Elsevier Inc. Terms and Conditions

Cell  2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

Cell. 2011 Mar 4;144(5):646-74

Copyright © 2011 Elsevier Inc. Terms and Conditions

##

http://www.cellsignal.com/common/content/content.jsp?id=science-pathways

Robbins Basic Pathology

Hallmarks of Cancer

Self-sufficiency in growth signals

Insensitivity to growth inhibitory signals

Evasion of cell death

Limitless replicative potential

Development of sustained angiogenesis

Ability to invade and metastasize

Genomic instability

Tumor-promoting inflammation

SELF-SUFFICIENCY IN GROWTH SIGNALS

Self-Sufficiency in Growth Signals

• Physiologic Growth
  • The binding of a growth factor to its specific receptor on the cell membrane
  • Transient and limited activation of the growth factor receptor, which in turn activates several signal-transducing proteins on the inner leaflet of the plasma membrane
  • Transmission of the transduced signal across the cytosol to the nucleus by second messengers or a cascade of signal transduction molecules
  • Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription
  • Entry and progression of the cell into the cell cycle, resulting ultimately in cell division

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Growth Factors

• Cancer cells synthesize the same growth factors to which they are responsive
• Glioblastomas
  • secrete platelet-derived growth factor (PDGF)
  • express the PDGF receptor
• Sarcomas
  • Make transforming growth factor-α (TGF-α)
  • TGF-α receptor
• Interaction with stroma
  • Tumor cells send signals to activate normal cells in the supporting stroma
  • Then the stromal cells produce growth factors that promote tumor growth

Growth Factor Receptors andNon-Receptor Tyrosine Kinases

Mutant receptor proteins:

Deliver continuous mitogenic signals to cells

Even in the absence of the growth factor in the environment

• Overexpression of growth factor receptors
  • Hyperresponsive to levels of the growth factor that would not normally trigger proliferation
• ERBB1 (EGF receptor)
  • Overexpressed in 80% of squamous cell carcinomas of the lung
  • 50% or more of glioblastomas
  • 80% to 100% of epithelial tumors of the head and neck
• HER2/NEU (ERBB2)
  • Amplified in 25% to 30% of breast cancers
  • Adenocarcinomas of the lung, ovary, and salivary glands
  • Sensitive to the mitogenic effects of small amounts of growth factors
  • A high level of HER2/NEU protein in breast cancer cells is a poor prognosis
  • Anti-HER2/NEU antibodies used in breast cancer treatment

Downstream Signal-Transducing Proteins

• They receive signal from receptors
• Carry signal to nucleus via
  • second messengers
  • cascade of phosphorylation
• If there is an autonomy in these signals there is continuous signal to nucleus
• RAS
• ABL

RAS protein

• Most commonly mutated proto-oncogene in human tumors
• 30% of all tumors contain RAS mutation
• More common in colon and pancreas carcinoma
• G protein
  • Phosphorylation via GTP

RAS

• Normally
  • active when bound to GTP
  • Deactivated by GTPase
  • GTPase-activating proteins (GAPs)
• When mutated
  • __ cannot dephosphorylate__
  • Remains active

Robbins Basic Pathology

GAPs

• GTPase-activating protein
• Neurofibromin-1 (NF-1)
  • loss-of-function mutation
  • activation of RAS
  • Neurofibromatosis develops

Robbins Basic Pathology

RAF/ERK/MAP kinase pathway

Active in 60% of melanomas

BRAF mutation seen in papillary thyroid carcinomas

Robbins Basic Pathology

ABL

• Non-receptor-associated-tyrosine kinase
• Chronic Myelogenous Leukemia
  • ABL translocates from Chr9 to Chr22
  • Fuses with BCR
  • Continuous activation
  • Also activates RAS pathway
• Targeted therapy is present
  • BCR-ABL kinase inhibitor (Gleevec)

Robbins and Cotran’s Pathological Basis of Diseases

Nuclear Transcription Factors

• MYC, MYB, JUN, FOS, and REL oncogenes
  • Regulate the expression of growth-promoting genes, such as cyclins

MYC

• Activate growth-promoting genes cyclin-dependent kinases (CDKs)
• Inhibit CDK inhibitors (CDKIs)
• Upregulating genes that promote aerobic glycolysis (Warburg effect)
• İncreased utilization of glutamine
• Translocation
  • t(8;14) Burkitt lymphoma
• Amplification
  • Breast, colon, lung
  • Neuroblastomas, Small cell cancers of lung (NMYC, LMYC)

Robbins and Cotran’s Pathological Basis of Diseases

Robbins and Cotran’s Pathological Basis of Diseases

Robbins and Cotran’s Pathological Basis of Diseases

Cyclins and Cyclin-Dependent Kinases

• Checkpoints
• G0 → G1
• G1 → S
  • Restriction point
  • Rate-limiting step

Checkpoints to prevent proliferation of abnormal DNA

Inhibit

tumor growth

Activate tumor growth

Robbins Basic Pathology

• Increasing expression of cyclin D or CDK4 is common in neoplasia
• Cyclin D
  • breast, esophagus, liver, and a subset of lymphomas and plasma cell tumors
• CDK4
  • **melanomas, sarcomas, and glioblastomas. **
• CDKI
  • disabled by mutation or gene silencing in many human malignancies
  • Germline mutations of CDKN2A
    • 25% of melanoma-prone
  • Somatically acquired deletion or inactivation of CDKN2A

Robbins Basic Pathology

Homework

Rous sarcoma virus

INSENSITIVITY TO GROWTH INHIBITORY SIGNALS

Tumor Supressor Genes

RB Gene: Governor of the Cell Cycle

• 13q14
• Retinoblastoma occurs as a similar disease both in sporadic and familial forms
• Familial disease is Autosomal Dominant trait
• RB gene homozygous loss in
  • breast cancer, small cell cancer of the lung, and bladder cancer
• Patients with retinoblastoma have increased risk of
  • Osteosarcoma and soft tissue sarcomas

Retinoblastoma

Figure 2, from Pediatr Radiol. Jun 2012; 42(6): 738–749. PMCID: PMC3530407

**Figure 7.4b ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

Knudson two-hit hypothesis

Robbins Basic Pathology

Robbins Basic Pathology

Does a cell become neoplastic when one Rb gene is mutated?

No

Tumor Suppressor Genes require loss of function of both alleles to become neoplastic

Which mechanisms cause loss of function in a gene?

Does a cell become neoplastic when one allele of proto-oncogene is mutated?

Robbins Basic Pathology

cyclin E transcription

Robbins Basic Pathology

HPV E7 protein mimics here

cyclin E transcription

Robbins Basic Pathology

TP53 GeneGuardian of the Genome

• Quiescence
  • Activation of temporary cell cycle arrest
• Senescence
  • Induction of permanent cell cycle arrest
• Apoptosis
  • Triggering of programmed cell death

Rb “senses” external signals, p53 monitors internal stress

p53 is activated by

Anoxia

Inappropriate oncoprotein activity

Damage to the integrity of DNA

p53 is a DNA damage response protein

p53

• Normally
  • p53 has a short half-life
  • After 20 minutes associates with MDM2 and destructed
• When cell is stressed
  • Protein kinases are activated
    • ATM (ataxia telangiectasia mutated)
  • Make post transcriptional modifications in p53
  • p53 is released from MDM2
  • p53 activity continues
• After repair
  • p53 induces MDM2 expression and p53 levels decrease to normal, cell cycle continues

Robbins Basic Pathology

p53-mediated cell cycle arrest

p53 induces transcription of CDKI gene CDKN1A (p21)

p21 protein inhibits cyclin–CDK complexes

Prevents phosphorylation of Rb

Arresting cells in the G1 phase

Time to repair DNA damage

p53-induced senescence

Involve global chromatin changes

Drastically and permanently alter gene expression

Permanent cell cycle arrest

p53-induced apoptosis

Irreversible DNA damage

pro-apoptotic genes such as BAX and PUMA

p53

• 70% of human cancers have a biallelic loss in p53
• Others have defects in genes upstream or downstream of TP53
• p53 is inhibited by oncogenic DNA viruses
  • Hepatitis B virus
  • possibly EBV

Li-Fraumeni syndrome

Inherit a mutant TP53 allele

25x more cancer by age 50

Sarcomas, breast cancer, leukemia, brain tumors, carcinomas of the adrenal cortex

Younger age

Multiple primary tumors

Transforming Growth Factor-β Pathway

• Potent inhibitor of proliferation
• TGF-β receptors I and II
  • Activate with dimerization
• Growth-suppressing activity
  • Transcriptional activation of CDKIs
• **Repression of growth-promoting genes **
  • MYC, CDK2, CDK4
  • Encoding cyclins A and E
• SMAD molecules
  • Transduce antiproliferative signals from the receptor to the nucleus
• TGF-β signaling activates epithelial-to-mesenchymal transition (EMT)

**Figure 5.21 ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

Transforming Growth Factor-β Pathway Alterations

• Mutations in
  • Type II TGF-β receptor
    • colon, stomach, and endometrium cancers
  • SMAD molecules
    • SMAD4 in pancreatic cancers
• 100% of pancreatic cancers and 83% of colon cancers, at least one component of the TGF-β pathway is mutated

**Figure 6.29d ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

Contact Inhibition

• Nontransformed cells are grown in culture
  • Proliferate until confluent monolayers are generated
  • Cell–cell contacts formed in these monolayers suppress further cell proliferation
• In cancer cells
  • No contact inhibition
  • Proliferate and pile on top of one another

Figure 3.7 from The Biology Of Cancer (2007) - Weinberg

**Figure 3.7a ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

**Figure 3.12 ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

Figure 3.7 from The Biology Of Cancer (2007) - Weinberg

E-cadherin

• E-cadherin mediates cell–cell contact in epithelial layers
• Tumor suppressor gene NF2 (neurofibromin-2, merlin), facilitates E-cadherin mediated contact inhibition
• Homozygous loss of NF2 → neural tumors
  • Neurofibromatosis
• E-cadherin is also regulated by APC (adenomatous polyposis coli gene)

No APC is present

β-Catenin is active independent of WNT status

WNT signal inhibits APC

β-Catenin enters nucleus

APC is active

β-Catenin is dectructed

Robbins Basic Pathology

No APC is present

β-Catenin is active independent of WNT status

WNT signal inhibits APC

β-Catenin enters nucleus

APC is active

β-Catenin is dectructed

Robbins Basic Pathology

β-Catenin is active in the nucleus

cyclin D1 and MYC transcribed for proliferation

TWIST and SLUG are expressed

They repress E-cadherin expression

Reduce contact inhibition

Robbins Basic Pathology

Adenomatous Polyposis Coli

• APC is a tumor suppressor gene
• With one mutant allele
  • Hundreds to thousands of adenomatous polyps in the colon
  • By age 20s
• When other allele also mutated
  • Malignant transformation
• APC mutations are seen in 70% to 80% of sporadic colon cancers
• Colonic cancers with normal APC genes have activating mutations of β-catenin
  • Refractory to the degrading action of APC

**Figure 7.22 ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

**Figure 7.24a ** _ The Biology of Cancer_ __ (© Garland Science 2007)__