Lecture 9.1 - Neoplasia 2.pdf

Cancer develops through gradual changes in cell morphology and properties: Glioma survival: What is cancer metastasis?: ◦Cancer defines as a population of cells that have lost their normal controls of growth and differentiation and are proliferating without check ◦Metastasis is the p...

Cancer develops through gradual changes in cell morphology and properties: Glioma survival: What is cancer metastasis?: ◦Cancer defines as a population of cells that have lost their normal controls of growth and differentiation and are proliferating without check ◦Metastasis is the process by which a tumour cell leaves the primary tumour, travels to a distant site via the circulatory system, and establishes a secondary tumour Metastasis: 5 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 tumour cells  Stages of metastasis: ◦Invasion - primary tumour cells enter circulation ◦Circulation to the secondary site of tumour growth ◦Colonisation - formation of secondary tumour How do tumour cells become invasive?: ◦An organ is composed of several tissues ◦Cancer cells need to change their epithelial properties, to lose their adhesion and to penetrate through potent physical barriers ‣ Basal lamina is part of connective tissue and cells cannot pass through it EMT: ◦Epithelial to mesenchymal transition Tumour invasion: ◦Translocation of cells across extracellular matrix barriers ◦Lysis of matrix protein by specific proteinases ◦Cell migration Components of invasion: ◦Matrix degrading enzymes  ◦Cell adhesion ◦Cell motility 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-, cysteine-, aspartyl- and metalloproteinase Matrix metalloproteinases (MMP): ◦16 members, subdivided into 4 groups, based on their structural characteristics and 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 Regulation of MMP: ◦MMP is controlled by an increased expression on a transcriptional level ◦MMPs are calcium-dependent proteases, which are synthesised as an inactive proenzymes and are activated by the cleavage of a propeptide ◦MMP activity is regulated by specific inhibitors, the tissue inhibitors of MMP (TIMPs). Binding TIMP to MMP is in a 1:1 stoichiometry ◦MMP2 and MMP9, which cleave type IV collagen the major constituent of basement membrane, are believed to be of special importance ◦MMPs (matrix metalloproteinases) help the cancer cells to invade the ECM - punch holes in membrane and connective tissue layer Cell attachment: ◦Integrin - cell-matrix adhesion: ‣ Heterodimeric transmembrane receptors consist of alpha and beta subunits ‣ Function to provide interactions between cells and macromolecules in the ECM ‣ Integrin can affect the transcription of MMP genes ◦E-cadherin/catenin adhesion complex - cell-cell adhesion: ‣ Most important cell-cell adhesion molecules (interactions between cells) ‣ Reduce expression of E-cadherin and catenin increase the invasiveness of tumour cells  Cell adhesion and metastasis: Cell migration: ◦Small Rho GTPase family ◦Motility promoting factors: ‣ Hepatocyte growth factor/scattering factor ‣ Insulin-like growth factor II ‣ Autotaxin What are the routes of metastasis?: ◦Lymphatics ◦Blood vessels ◦Coelemic spaces Lymphatics: ◦Spread to local and distant lymph nodes ◦Frequent route of spread of carcinomas ◦Can involve lymphatics of lung Vascular spread: ◦ Spread through capillaries and veins to various organs ◦Common sites are lung, liver, bone and brain Intravasation:  The blood - a hostile environment: ◦Cells are normally anchorage-dependent (anoikis) ◦Shear forces tear cells apart Where do they go?: ◦Metastatic tropism Colonisation: ◦First, micrometasteses Dormant micrometasteses are viable:  Why don't all malignant cells metastasise?: ◦Cells may invade and circulate ◦May get to distant site but environment may not be appropriate for growth of those cells ‣ Incorrect receptors ‣ Metabolic factors ‣ Failure of angiogenesis "Seed and soil" Metastatic inefficiency: ◦A sequence of inefficient steps What effects do tumours have?: ◦Depends on: ‣ Site of tumour ‣ Extent of local spread ‣ Site of metastasis ‣ Extent of metastatic spread ‣ Functional effects ◦In certain sites, a small tumour can have devastating effects ◦People can survive for some time with very extensive metastatic spread Local effects of neoplasms?: ◦Benign: ‣ Cause compression - pressure atrophy; altered function e.g. pituitary ‣ In a hollow viscus, causes partial or complete obstruction ‣ Ulceration of surface mucosa ‣ Space occupying lesion - brain ◦Malignant: ‣ Tend to destroy surrounding tissue ‣ In a hollow viscus, causes partial or complete obstruction, constriction ‣ Ulceration - becomes a problem ‣ Infiltration around and into nerves, blood vessels, lymphatics ‣ Space occupying lesion - brain Systemic effects of neoplasms: ◦Haemotological: ‣ Anaemia:  Due to ulceration (benign and malignant) Infiltration of bone marrow (leukaemia, metastasis) Haemolysis ‣ Low white cell and platelets Infiltration of bone marrow, treatment ‣ Thrombosis Carcinoma of pancreas ◦Endocrine: ‣ Excessive secretion of hormones - benign and malignant neoplasms of endocrine glands e.g. parathyroid hormone, corticosteroids ‣ Ectopic hormone secretion - ACTH by small cell carcinoma of bronchus ◦Neuromuscular: ‣ Problems with balance ‣ Sensory/sensorimotor neuropathies ‣ Myopathy and myasthenia ‣ Progressive multifocal leucoencephalopathy ‣ Not due to metastasis to brain Why do neoplasms kill people?: ◦Local effect e.g. brain, perforation, haemorrhage - benign or malignant ◦Replacement of essential body organs - malignant