Neoplasia3-Metastasis Features of M

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NEOPLASIA-3:

NEOPLASIA-3 Dr. R. Sasank

Neoplasia -3 Lesson Plan:

Neoplasia -3 Lesson Plan Definitions Nomenclature Benign Vs Malignant Epidemiology Molecular basis of cancer Carcinogenic Agents & cellular interaction Host Defense , tumor immunity Clinical Aspects

Differentiation:

Differentiation Well differentiated Sq Cell Ca Moderately Diff Sq Cell Ca Poorly Diff Sq Cell Ca Undifferentiated Tumor

Anaplasia:

Anaplasia Nothing but Dedifferentiation Reverse of differentiation Characteristic of Malignancy

Dysplasia- Respiratory Epithelium:

Dysplasia- Respiratory Epithelium

Capsulated fibroadenoma:

Capsulated fibroadenoma

Benign vs Malignant tumors-1:

Benign vs Malignant tumors-1 Feature Benign Malignant Rate of growth Progressive,Slow. Variable. Mitoses few and normal Mitoses more frequent & abnormal Differentiation Well differentiated Poor Differentiat & anaplasia LOCAL INVASION Cohesive growth. Poorly cohesive Capsule & BM not breached and infiltrative. Metastasis Absent May occur

Biology of tumor growth.:

“clonal” Biology of tumor growth.

Features of Malignant Tumors:

Features of Malignant Tumors Cellular features Local invasion Capsule Basement membrane Metastasis Unequivocal sign of malignancy Seeding of body cavities Lymphatic Hematogenous

Metastasis Overview :

Metastasis Overview What is metastasis? Molecular mechanisms of metastasis Signalling pathways involved in metastasis

Invasion & Metastasis:

Invasion & Metastasis Seeding Lymphatic spread Blood Spread Invading into surrounding Tissue Three ways tumors metastasize

Components of invasion:

Components of invasion Translocation of cells across extracellular matrix barriers Lysis of matrix protein by specific proteinases Cell migration Matrix degrading enzymes Cell adhesion Cell motility

Invasion Factors:

Invasion Factors Detachment (loosening) of the tumor cells Attachment to matrix Degradation of ECM, e.g., collagenase Migration of tumor cells I N V A S I O N F a c T o R S

Metastasis-Pathway:

Metastasis-Pathway Direct Spread Lymphatic spread Hematogenous spread Three ways of tumors metastasing

Pathways of Metastasis-(Direct):

Pathways of Metastasis-( Direct) Direct Spread Direct seeding of body cavities or surfaces Peritoneal cavity, Pleural, Pericardial, Subarachnoid, Joint spaces Three ways of tumors metastasing

Pathways of Metastasis-(Hematogenous):

Pathways of Metastasis-( Hematogenous) Veins are easier to invade than arteries Liver and lungs are most common metastatic destinations Some tumors like other sites better: prostate → bone most lung cancers → adrenals, brain Sarcomas like to spread this way (but so do carcinomas) Three ways of tumors metastasing

Hematogenous Spread- a sarcoma:

Hematogenous Spread- a sarcoma

Sarcoma metastatic to lung:

Sarcoma metastatic to lung

Pathways of Metastasis-(Lymphatic):

Pathways of Metastasis-( Lymphatic) Three ways of tumors metastasing Example of breast cancer Halsted radical mastectomy Sentinel node biopsy Prognostic Number of nodes is imp in TNM staging Therapeutic Overall risk of recurrence Extent of nodal involvement Histologic grade and other considerations “ Adjuvant ” chemotherapy

Breast Carcinoma & Nodes:

Breast Carcinoma & Nodes

Metastasis into Liver:

Metastasis into Liver

Lymph node with metastatic adenocarcinoma:

Lymph node with metastatic adenocarcinoma

Tumor in lymphatic:

Tumor in lymphatic

Tumor in lymph node:

Tumor in lymph node

I) What is cancer metastasis? :

I) What is cancer metastasis? Metastasis is the process by which a tumor cell leaves the primary tumor, travels to a distant site via the circulatory system, and establishes a secondary tumor.

Forms of cancer metastasis :

Forms of cancer metastasis Simple Metastasis Tumor Embolus Angiogenesis

Preferential metastatic sites:

Preferential metastatic sites Primary tumour Common distant site (s) Breast ’ adenocarcinoma Bone, brain, adrenal Prostate adenocarcinoma Bone Lung small cell carcinoma Bone, brain, liver Skin cutaneous melanoma Brain, liver, Bowel Thyroid adenocarcinoma Bone Kidney clear cell carcinoma Bone, liver, thyroid Testis carcinoma Liver Bladder carcinoma Brain Neuroblastoma Liver, adrenal

Reason for organ selectivity:

Reason for organ selectivity Mechanistic theory: Determined by the pattern of blood flow. “ Seed and soil ” theory: The provision of a fertile environment in which compatible tumor cells could grow

Determining factors for Metastasis:

Determining factors for Metastasis Appropriate growth factors Appropriate extra-cellular matrix environment Compatible adhesion sites on the endothelium Selective chemotaxis at which the organ producing some soluble attraction factors to the tumor cells

Major steps in metastasis:

Major steps in metastasis Invasion and infiltration of surrounding normal host tissue with penetration of small lymphatic or vascular channels; Release of neoplastic cells, either or single cells or small clumps, into the circulation; Survival in the circulation; Arrest in the capillary beds of distant organs; Penetration of the lymphatic or blood vessel walls followed by growth of the disseminated tumor cells

Steps in metastasis:

Steps in metastasis

a) Matrix degrading enzymes:

a) Matrix degrading enzymes Required for a controlled degradation of components of the extracellular matrix (ECM) The proteases involved in this process are classified into Serine proteases, cysteine-, aspartyl-, and metalloproteinase .

Matrix metalloproteinases (MMP):

Matrix metalloproteinases (MMP) 16 members (4 groups) based on their structur & substrate specificities Soluble and secreted groups; collagenase, gelatinase and stromelysins Membrane type (MT-MMP) group are anchored in the plasma membrane A zinc ion in the active centre of the protease is required for their catalytic activities.

Serine proteases:

Serine proteases Serine protease involved in ECM degradation are plasmin, plasminogen activators and cathepsin G.

Plasminogen activator:

Plasminogen activator Two main types : urokinase (uPA) and tissue (tPA). uPA is bound to the surface of tumor cells by means of a specific receptor (uPAR) There are specific inhibitors (PAI-1 and PAI-2) for the PA.

Interaction between tumour cells and the surrounding connective tissue :

Interaction between tumour cells and the surrounding connective tissue

Cell adhesion and metastasis :

Cell adhesion and metastasis

b) Cell attachmen:

b) Cell attachmen 1. Integrin: cell-matrix adhesion Heterodimeric transmembrane receptors consists of a and b subunits Function to provide interactions between cells and macromolecules in the ECM signaling 2. E-cadherin/catenin adhesion complex: cell-cell adhesion

c) Cell migration :

c) Cell migration Small Rho GTPase family Motility promoting factors

Cell movement:

Cell movement

Motility promoting factors :

Motility promoting factors Hepatocyte growth factor/scattering factor HGF normally acts as a paracrine growth factor, but in tumor cells it can act as an autocrine Insulin-like growth factor II Autotaxin

HGF induce cell scattering and invasion:

HGF induce cell scattering and invasion

TUMOR ANGIOGENESIS:

TUMOR ANGIOGENESIS A blood vessel must be 1-2 mm from a cell? Activation of VEGF and FGF-b Tumor size is regulated (allowed) by angiogenesis/anti-angiogenesis balance

METASTATIC GENES?:

METASTATIC GENES? NM23 KAI-1 KiSS

Metastasis Summery.:

Metastasis Summery . TRANSFORMATION  GROWTH  BM INVASION  ANGIOGENESIS INTRAVASATION  EMBOLIZATION  ADHESION  EXTRAVASATION  METASTATIC GROWTH  etc

Epidemiology:

Epidemiology Cancer incidence

Epidemiology of Tumors:

Epidemiology of Tumors Cancer incidence Environmental variables Age Heredity

Cancer Incidence (Statistics):

Cancer Incidence (Statistics) 1.4 million new cases of cancer last year 565,000 deaths from cancer last year Cancer is 2 nd leading cause of death (after heart disease) Most common cancers Men: Prostate Women: Breast Deadliest cancers Men: Lung Women: Lung

Cancer Deaths-Male:

Cancer Deaths-Male

Cancer Deaths-Female:

Cancer Deaths-Female

Major Cause of death:

Major Cause of death

Most common cancer:

Most common cancer

Cancer Incidence:

Cancer Incidence

Cancer Incidence:

Cancer Incidence Decrease in death rates for: Cervical cancer (pap smears) Colon cancer (earlier detection) Breast cancer (earlier detection) Lung cancer in men (less smokers) Some types of leukemia (new treatment) Increase in death rates for: Lung cancer in women (more smokers) Death rates changed in past few years

Environmental Variables:

Environmental Variables Breast cancer death rate in US is 5x that in Japan! Stomach cancer death rate in Japan is 7x that in US! Liver cancer infrequent in US, common in Africa. Probably due to environmental (not hereditary) factors. Most sporadic cancers are caused by environmental factors.

Environmental Variables:

Environmental Variables Sunlight: skin cancer Smoking: lung cancer Alcohol: liver, breast cancers HPV: cervical carcinoma Environmental carcinogens

Occupational carcinogens:

Occupational carcinogens Asbestos roofing, tiles mesothelioma Benzene light oil, solvents leukemia Beryllium missile fuel lung cancer Ethylene oxide ripening agents, fumigants leukemia Radon uranium decay, mines lung cancer Vinyl chloride refrigerants angiosarcoma and liver cancer Nickel welding, ceramics nose and liver cancers Cadmium batteries prostate cancer Occupational carcinogens

Age:

Age Cancer is most frequent at the two extremes of age. Elderly Frequency of cancer increases with age Most cancer deaths occur between 55-75 Children 10% of all childhood deaths Leukemia/lymphoma, CNS tumors, sarcoma

Heredity:

Heredity Inherited cancer syndromes Familial cancers Syndromes of defective DNA repair Three categories of hereditary cancer

Heredity:

Heredity Inherited cancer syndromes Dominantly inherited Retinoblastoma Familial polyposis coli Three categories of hereditary cancer

Familial polyposis col:

Familial polyposis col

Heredity:

Heredity Inherited cancer syndromes Familial cancers Most common sporadic cancers have familial forms too Breast, colon, ovary, brain Occur earlier, are often deadlier Three categories of hereditary cancer

Heredity:

Heredity Inherited cancer syndromes Familial cancers Syndromes of defective DNA repair Recessively inherited Xeroderma pigmentosum Three categories of hereditary cancer

Customs and Habits causing cancer:

Customs and Habits causing cancer Khini cancer Chutta cancer Beetle leaf and nut Khangri cancer Dhoti cancer Breast, cervical Circumcised men Jawari roti Smoked Fish

Thank You:

Thank You