patoloji-ders-notlari

Title

Serdar Balcı

Hallmarks of Cancer-2

Serdar BALCI, MD

EVASION OF CELL DEATH

Resistance to Apoptosis

Extrinsic Pathway

TNF receptor CD95 (Fas) binds to ligand CD95L

Trimerization of the receptor and cytoplasmic death domains

Attract the intracellular adaptor protein FADD

Procaspase-8 activated by cleavage into smaller subunits

Caspase-8 activates downstream caspase-3

Cleaves DNA and other substrates

Cell death

Robbins Basic Pathology

Intrinsic Pathway

Withdrawal of survival factors, stress, and injury

Permeabilization of the mitochondrial outer membrane

Cytochrome c leaks into the cytosol

Binds to APAF-1

Activates caspase-9

Cleave and activate the executioner caspases

Robbins Basic Pathology

• Pro-apoptotic proteins
  • BAX and BAK
  • Directly promote mitochondrial permeabilization
• Anti-apoptotic proteins
  • BCL2 and BCL-XL
  • inhibit BAX and BAK
• BH3-only proteins
  • BAD, BID, and PUMA
  • Regulate the balance between the pro- and anti-apoptotic proteins

Follicular B cell Lymphoma

• t(14;18) (q32;q21) translocation
• 14q32
  • chromosomal locus for Ig heavy-chain genes
  • Transcriptionally active
• 18q21
  • BCL2
• When they come together
  • Overexpression of the BCL2 protein
• B cells are protected from apoptosis
• They are indolent tumors
  • Since the change is not actively proliferating cells but preventing from death

Autophagy

Stress may also induce cells to consume their components

Cancer cells may accumulate mutations to avoid autophagy

Cancer cells use autophagy to survive in unfriendly climates or during therapy

LIMITLESS REPLICATIVE POTENTIAL

Telomer Shortening in normal human cells

Capacity of 60 to 70 doublings

Shortening of telomeres

Recognized by the DNA repair machinery as double-stranded DNA breaks

Then enter senescence

Robbins Basic Pathology

Telomer shortening in neoplasia

TP53 or RB mutations, cell is forced to replicate

Nonhomologous end-joining pathway is activated

Joining the shortened ends of two chromosomes.

Dicentric chromosomes

Pulled apart at anaphase

Resulting in new double-stranded DNA breaks

Genomic instability due to repeated bridge–fusion–breakage cycles

Apoptosis may occur

Robbins Basic Pathology

Rubin’s Pathology 7th Ed

• Telomere maintenance is seen in virtually all types of cancers
• Upregulation of the enzyme telomerase
• Colon tumors
  • Early lesions have high genomic instability, low telomerase
  • Malignant cells have complex karyotype, high telomerase

Robbins Basic Pathology

Robbins Basic Pathology

DEVELOPMENT OF SUSTAINED ANGIOGENESIS

Tumor Vessels

• Tumors cannot enlarge beyond 1-2 mm in diameter unless they are vascularized
• Cancer cells and large benign tumors can stimulate neoangiogenesis
  • New vessels sprout from previously existing capillaries
• Vasculogenesis
  • Endothelial cells are recruited from the bone marrow
• Tumor vasculature is abnormal
  • Vessels are leaky and dilated
  • Haphazard pattern of connection

Effects of vascularization on tumor

• Supplies needed nutrients and oxygen
• Newly formed endothelial cells stimulate the growth of adjacent tumor cells
  • Secrete growth factors insulin-like growth factors, PDGF, and granulocyte-macrophage colony-stimulating factor
• Required for continued tumor growth
• Necessary for metastasis

Factors in Angiogenesis

• Vascular endothelial growth factor (VEGF)
  • Angiogenesis inducer
• Thrombospondin-1 (TSP-1)
  • Angiogenesis inhibitor
• Normal p53 induces synthesis of TSP-1
• Production of angiogenic factors and/or loss of angiogenesis inhibitors
  • Directly by the tumor cells themselves
  • Inflammatory cells (macrophages)
  • Other stromal cells associated with the tumors

Production of Factors in Angiogenesis

• Proteases
  • elaborated by the tumor cells directly or from stromal cells
  • regulate the balance between angiogenic and anti-angiogenic factors
• Angiogenic basic FGF stored in the extracellular matrix (ECM)
  • Released by proteases
• Angiogenesis inhibitors—angiostatin, endostatin, and vasculostatin—are produced by proteolytic cleavage of plasminogen, collagen, and transthyretin, respectively
• TSP-1 is produced by stromal fibroblasts themselves in response to signals from the tumor cells

Normoxia

HIF-1α activates transcription of VEGF

HIF-1α is continuously produced

von Hippel–Lindau protein (VHL) binds to HIF-1α

**Ubiquitination **

Destruction of HIF-1α

No VEGF production in normal oxygen levels

Hypoxia

Tumor that has reached a critical size

Lack of oxygen prevents HIF-1α recognition by VHL

HIF-1α is not destroyed

HIF-1α translocates to the nucleus

Activates transcription of its target genes, such as VEGF

Angiogenesis occurs

Anti-VEGF antibody used in the treatment

von Hippel–Lindau (VHL) syndrome

• VHL acts as a tumor suppressor gene
• Germline mutations of the VHL gene
  • Hereditary renal cell cancers
  • Pheochromocytomas
  • Hemangiomas of the central nervous system
  • Retinal angiomas
  • Renal cysts