patoloji-ders-notlari

Title

Serdar Balcı

Hallmarks of Cancer-3

Serdar BALCI, MD

ABILITY TO INVADE AND METASTASIZE

Metastatic Cascade

Local invasion

Intravasation into blood and lymph vessels

Transit through the vasculature

Extravasation from the vessels

Formation of micrometastases

Growth into macroscopic tumors

Robbins Basic Pathology

Invasion of Extracellular Matrix (ECM)

• Tumors interact with different matrix elements
  • Basement membrane
  • Interstitial connective tissue
  • Vascular basement membrane, exit, enter
  • New interstitial connective tissue

Robbins Basic Pathology

Invasion of Epithelial Basement Membrane

Loosening of tumor cells

Degredation

Attachment to ECM

Locomotion

Robbins Basic Pathology

• E-cadherin
  • Interstitial glue
  • Antigrowth signal, keeps β-catenin in cytoplasm
• E-cadherin function is lost in almost all epithelial cancers
  • Mutational inactivation of E-cadherin genes
  • Activation of β-catenin genes
  • Inappropriate expression of the SNAIL and TWIST which suppress E-cadherin expression

E-cadherin loss leads to single cell infiltration pattern

Lobular Breast Carcinoma

Diffuse infiltrative, poorly-cohesive adenocarcinomas of stomach

Rosai and Ackerman’s Surgical Pathology

• Tumor cells
  • Secrete proteolytic enzymes themselves
  • Induce stromal cells (fibroblasts, inflammatory cells) to secrete
• Proteolytic enzymes
  • Matrix metalloproteinases (MMPs)
  • Cathepsin D
  • Urokinase plasminogen activator

• MMPs
  • Remodeling insoluble components of the basement membrane and interstitial matrix
  • Releasing ECM-sequestered growth factors
• Cleavage products of collagen and proteoglycans
  • chemotactic, angiogenic, and growth-promoting effects
• MMP-9
  • Gelatinase
  • Cleaves type IV collagen of the epithelial and vascular basement membrane
  • Stimulates release of VEGF from ECM-sequestered pools

• Normal epithelial cells
  • Integrins
  • Basement membrane laminin and collagens
  • Polarized at their basal surface
  • Maintain the cells in a resting, differentiated state
  • Loss of adhesion in normal cells leads to induction of apoptosis

• In tumor
  • Cells resist apoptosis
  • Matrix is modified to promote invasion and metastasis
  • Cleavage of the basement membrane proteins (collagen IV, laminin), by MMP-2 or MMP-9
  • New sites formed for receptors on tumor cells
  • Stimulate migration

• Complex, multistep process
• Many families of receptors and signaling proteins
• Actin cytoskeleton
• Chemotactic activity from
  • Tumor cell–derived autocrine motility factors
  • Cleavage products of matrix components
  • Insulin-like growth factors I and II
  • Stromal cells paracrine effectors of cell motility
    • Hepatocyte growth factor/scatter factor (HGF/SCF)

Vascular DisseminationHoming of Tumor Cells

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

**Figure 14.5c ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

Robbins Basic Pathology

SNAIL and TWIST

• Transcription factors
• Promote epithelial-to-mesenchymal transition (EMT)
  • Carcinoma cells downregulate epithelial markers (E-cadherin)
  • Upregulate mesenchymal markers (vimentin, smooth muscle actin)
• Phenotypic alterations
  • Polygonal epithelioid cell shape to a spindly mesenchymal shape
  • Increased production of proteolytic enzymes

**Figure 14.14b ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

**Figure 14.19b ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

Robbins Basic Pathology

**Figure 14.2a ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

**Figure 14.9 ** _ The Biology of Cancer_ __ (© Garland Science 2007)__

Robbins Basic Pathology

Homing - Organ tropism

Metastasis occur according to dissemination site and vascular pathway

Although skeletal muscle has abundant muscle supply, it is not a site of metastasis

Expression of adhesion molecules by tumor cells whose ligands are expressed preferentially on the endothelium of target organs

Expression of chemokines and their receptors

Human breast cancer cells express high levels of the chemokine receptors CXCR4 and CCR7

The ligands for these receptors (chemokines CXCL12 and CCL21) are highly expressed only in those organs to which breast cancer cells metastasize

The Scientist Cancer’s Vanguard Exosomes are emerging as key players in metastasis. April 1, 2016

Robbins Basic Pathology

Robbins Basic Pathology

Robbins Basic Pathology

Robbins and Cotran’s Pathological Basis of Diseases

Metastasis-to-metastasis seeding

occurs either by a linear or by a branching

pattern of spread

Nature. 2015 Apr 16;520(7547):353-7

REPROGRAMMING ENERGY METABOLISM

O2 metabolism

• Shifts from mitochondrial to glycolysis
  • Even when O 2 __ is enough__
  • Warburg effect
• Tumors need ATP __ __ for rapid growth
• But they also need building blocks for rapid growth
• They use pyruvate in biosynthetic pathways instead of using it for ATP supply

The Scientist Metabolic Reprogramming How cancer cells fuel their rapid growth April 1, 2016

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http://www.youtube.com/watch?v=kYmLQP2M-qo

Defects in tricyclic carbon cycle

Isocitrate dehydrogenase mutations cause accumulation of byproducts

Most important discovery in malignant CNS tumors

Cancer Cell. 2010 Jan 19;17(1):7-9

Succinate dehydrogenase

Paraganglioma

Fumarate hydratase

Kidney cancers

Oncogene (2006) 25, 4675–4682

EVASION OF THE IMMUNE SYSTEM

Evasion of the Immune System

Most tumors arise in immunocompetent hosts

Immune system fails to recognize or eliminate

Tumor immunity and hosts response to tumor

https://www.youtube.com/watch?v=K09xzIQ8zsg

https://www.youtube.com/watch?v=K09xzIQ8zsg

https://www.youtube.com/watch?v=K09xzIQ8zsg

https://www.youtube.com/watch?v=K09xzIQ8zsg

https://www.youtube.com/watch?v=K09xzIQ8zsg

https://www.youtube.com/watch?v=K09xzIQ8zsg

https://www.youtube.com/watch?v=K09xzIQ8zsg

GENOMIC INSTABILITY AS AN ENABLER OF MALIGNANCY

DNA repair

• DNA repair is defected in some inherited cancer syndromes
• Normal DNA repair systems:
  • Mismatch repair
  • Nucleotide excision repair
  • Recombination repair

http://www.nobelprize.org/

http://www.nobelprize.org/

http://www.nobelprize.org/

http://www.nobelprize.org/

Hereditary Nonpolyposis Colon Cancer Syndrome

Familial carcinomas of the cecum and proximal colon

Defects in genes of DNA mismatch repair

When DNA is repaired, these genes act as “spell checkers.”

Without them errors accumulate at an increased rate

Microsatellite instability (MSI) occurs

Xeroderma Pigmentosum

Ultraviolet rays in sunlight cause cross-linking of pyrimidine residues

Prevent normal DNA replication

Inherited loss of this repair causes many skin tumors

Diseases with Defects in DNA Repair by Homologous Recombination

Autosomal recessive

Hypersensitivity to other DNA-damaging agents

Ionizing radiation (in Bloom syndrome and ataxia-telangiectasia)

DNA cross-linking agents, such as nitrogen mustard (in Fanconi anemia)

BRCA1 and BRCA2

DNA repair genes

When activitiy is lost leads to Hereditary and sporadic breast and ovarian tumors

**Genes involved in homologous recombination DNA repair pathway **

Hereditary breast cancer

Women with BRCA1 mutations higher risk of epithelial ovarian cancers, and men have a slightly higher risk of prostate cancer

Mutations in the BRCA2 gene increase the risk of breast cancer in both men and women, as well as cancer of the ovary, prostate, pancreas, bile ducts, stomach, melanocytes, and B lymphocytes

Cancers Resulting From Mutations Induced by Regulated Genomic Instability: Lymphoid Neoplasms

A special type of DNA damage plays a central role in the pathogenesis of tumors of B and T lymphocytes. As described earlier, adaptive immunity relies on the ability of B and T cells to diversify their antigen receptor genes. Early B and T cells both express a pair of gene products, RAG1 and RAG2, that carry out V(D)J segment recombination, permitting the assembling of functional antigen receptor genes. In addition, after encountering antigen, mature B cells express a specialized enzyme called activation-induced cytosine deaminase (AID), which catalyzes both immunoglobulin gene class switch recombination and somatic hypermutation

TUMOR-PROMOTING INFLAMMATION AS ENABLER OF MALIGNANCY

Inflammation, Friend or Enemy

• Persistent chronic inflammation cause tumor
• Increased risk of malignancy in
  • Barrett esophagus
  • Ulcerative colitis
  • H. pylori gastritis
  • Hepatitis B and C
  • Chronic pancreatitis
• Continuous regeneration, decreased apoptosis, increased proliferation, accumulates defects
• Neutrophils
  • Secrete reactive oxygen radicals
  • DNA damage
• Inflammation against tumor
• Amount changes in tumors
• Thought to be protective, trying to destroy tumor
• But
  • They release growth factor
  • Increase DNA damage
  • Increase epithelial-mesenchymal transition

Specific Drugs for Specific FeaturesTargetted Therapy

Robbins Basic Pathology