neoplasia 2 update.pdf

Neoplasia II Invasion ,Metastasis and effects of tumors Dr. NADA HAMZAH SHAREEF WHAT IS INVASION? Ability of cells to break through basement and then spread through the stroma (extra cellular matrix). Into the surrounding tissue. In-Situ Carcinoma--------- Invasive Carcinoma...

Neoplasia II Invasion ,Metastasis and effects of tumors Dr. NADA HAMZAH SHAREEF WHAT IS INVASION? Ability of cells to break through basement and then spread through the stroma (extra cellular matrix). Into the surrounding tissue. In-Situ Carcinoma--------- Invasive Carcinoma In lymphatic/vascular channels Characteristic of malignant cells All benign tumors grow as cohesive masses that remain localized. Benign tumors lack the capacity to infiltrate, invade or metastasize to distant sites. Metastasis Metastasis is the spread of a tumor to sites that are discontinuous with the primary tumor site. Metastasis marks a tumor malignant. The invasiveness of cancers permits them to penetrate blood vessels, lymphatics and body cavities, causing distant spread (Metastasis). Cancers differ in their ability to metastasize Invasion and metastasis are biologic hallmarks of malignant tumors For tumor cells to break loose from a primary mass, enter blood vessels or lymphatics, and produce a secondary growth at a distant site, they must go through a series of step (The metastatic cascade) The metastatic cascade Sequential steps involved in the hematogenous spread of a tumor - (“loosening up”) of tumor cell-cell interactions -Degradation of ECM Attachment to novel ECM components(endothelial basement membrane). -Migration of tumor cells and homing and colonization.  Invasion of Extracellular Matrix Two types of ECM: 1. Basement membrane (BM) and 2. Interstitial connective tissue Composition: ECM is made up of collagens, glycoproteins, and proteoglycans Sequence of events in the invasion of epithelial basement membranes by tumor cells: Tumor cells detach from each other because of reduced adhesiveness, then secrete proteolytic enzymes, degrading the basement membrane. Binding to proteolytically generated binding sites And tumor cell migration follow  U N I V E R S I T Y O F B A SR A H AL - Z A H R A A M E D I C A L C O L L EGE 1 Dissociation of cells from one another (“loosening up”) of tumor cell-cell interactions As a result of alterations in intercellular adhesion molecules Normal cells are bound together by adhesion molecules Cell-cell interactions are mediated by the cadherin family of transmembrane glycoproteins Intracellularly the E-cadherins are connected to β-catenin and the actin cytoskeleton  CADHERINS are calcium dependent glycoproteins present at cell membrane. They interact homotypically between cells to bind them together Linked to the actin cytoskeleton by catenins. Reduced expression and alterations in interactions in cancer cells, allowing cells to move apart INTEGRINS glycoproteins composed of two subunits: α+β Many biological functions eg leukocyte adhesion, platelet adhesion. Receptors for different components of the basement membrane eg. Fibronectin, collagen Reduced expression of integrins modifies the contact between the cell and stroma allowing movement 2-Local degradation of the basement membrane and interstitial connective tissue Elaboration of proteases enzymes by – Tumor cells themselves or – Stromal cells [induced by tumor cells] Malignant cells synthesize factors that stimulate other cells (eg.fibroblasts) to synthesize more enzymes. * Many different families of proteases – Matrix metalloproteinases (MMPs) – Cathepsin D & – Urokinase plasminogen activator – Zinc dependent enzymes MMPs Tumors either elaborate large quantities of MMPs or they may reduce the concentrations of MMP-inhibitors They regulate tumor invasion by: Dissolving components of the BM & interstitial matrix Releasing ECM-sequestered growth factors – Cleavage products of collagen and proteoglycans also have chemotactic, angiogenic, and growth-promoting effects Eg: MMP9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular basement membrane and also stimulates release of VEGF from ECM-sequestered pools 3 - Attachment to novel ECM components Normal epithelial cells have receptors, such as integrins, for basement membrane laminin and collagens that are polarized at their basal surface – These receptors help to maintain the cells in a resting, differentiated state Loss of adhesion in normal cells leads to induction of apoptosis [tumor cells are resistant to this form of cell death] The matrix itself is modified in ways that promote invasion and metastasis malignant cell Motility – Eg: cleavage of the basement membrane proteins collagen IV and laminin by MMP2 or MMP9 generates novel sites that bind to receptors on tumor cells and stimulate migration 4 – Migration of tumor cells – Locomotion Cell migration can be divided into single cell migration collective cell migration (Ameboid migration ) Tumor cells push themselves through the degraded basement membranes and zones of matrix proteolysis Mediated by: –cell derived motility factors –autocrine signaling factors –Cleavage products of matrix proteins –Other WHY DON’T ALL MALIGNANT CELLS METASTASISE? Cellsmay 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”  Pathways of metastasis (secondary tumor deposits )are: 1.Lymphatic spread (Usually Carcinoma) 2. Haematogenous spread (Usually Sarcoma) 3. Direct seeding of body cavities or surfaces (Krukenberg tumor) Lymphatic Spread (LC) Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas. The lymphatic spread involves deposition of cancer cells in the draining lymphnodes. Involvement of lymph nodes is important for assessing course of the disease (stage) and selecting suitable therapeutic strategies. Lymphatic invasion by tumor. (a) Histology of invasion of lymphatic vessel. (b) Tumor in para-aortic lymph nodes. Micrograph (a) shows malignant cells (M) in a small lymphatic vessel. Cells break off from the primary tumor, enter small lymphatics and are carried to lymph nodes, where they frequently grow as metastases. The macroscopic appearance of tumor in nodes is shown in (b); the nodes (N) are enlarged and replaced by tumor which, in this instance, originated from the testis. Hematogenous Spread (HS) Hematogenous spread through capillaries and veins is typical route for metastsis of sarcoma. The liver, the lungs, bone marrow, are most frequently involved in hematogenous metastasis. Main sites of blood-borne metastasis. (a) Sites of hematogenous metastasis. (b) Metastasis in bone. (c) Metastasis in brain. (d) Metastasis in liver. (e) Metastasis in adrenals. (f) Metastasis in lungs. To Lung Can occur with a wide range of malignant neoplasms. Sarcomas eg. Osteosarcoma Carcinomas eg. breast, stomach, large intestine Kidney (cannonball) Testis eg. malignant teratoma To Liver Common site for carcinomas of large intestine (portal vein). Bronchial carcinoma. Breast Carcinoma To Bone Can cause destruction of bone Bronchial carcinoma Breast carcinoma Thyroid carcinoma Renal carcinoma Cause production of dense bone (osteosclerosis) Prostate To Brain Can cause problems within the brain and the meninges Metastasis from eg. Bronchial carcinoma Breast carcinoma Testicular carcinoma Malignant melanoma  Seeding of Body Cavities and Surfaces Peritoneal cavity mostly involved in seeding pathway but pleural, pericardial, subarachnoid spaces may also involved. Example: i. Krukenberg tumor of ovary: when GIT cancer metastasis in the ovarian surface. ii. Pseudomyxoma peritonei: When Mucous secreting carcinoma of appendix fill the peritoneal cavity with gelatinous neoplastic mass. WHAT EFFECTS DO TUMOURS HAVE? LOCAL EFFECTS OF NEOPLASMS BENIGN Cause compression -pressure atrophy altered function eg. Pituitary adenoma -In a hollow viscus cause partial or complete obstruction. -Ulceration of surface mucosa. -Space occupying lesion brain. LOCAL EFFECTS OF NEOPLASMS MALIGNANT -Tend to destroy surrounding tissue. -In a hollow viscus cause partial or complete obstruction, constriction. -Ulceration. -Infiltration around and into nerves, blood vessels, lymphatics. Space occupying lesion - brain SYSTEMIC EFFECTS OF NEOPLASMS Cancer Cachexia Progressive loss of body fat and lean body mass accompanied by weakness, anorexia, and anemia Weight loss results equally from loss of fat and muscle Due to increased basal metabolic rate despite reduced food intake Malaise Pyrexia Haematological 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 PTH by small cell carcinoma of bronchus ADH by small cell carcinoma of bronchus Neuromuscular -Problems with balance. Sensory/ motor neuropathies. Myopathy and myasthenia. Progressive multifocal leucoencephalopathy. May mimic metastasis to brain. Skin Increased pigmentation Pruritis (itching),jaundice Herpes zoster Deratomyositi s Paraneoplastic Syndromes Symptom complexes in cancer-bearing individuals that cannot readily be explained, either by the local or distant spread of the tumor or by the elaboration of hormones.  Paraneoplastic Syndromes Significance: 1. May present the earliest manifestation of an occult neoplasm 2. May represent significant clinical problems in the affected patients 3. May mimic metastatic disease which may complicate treatment 1. Endocrinopathies Ectopic hormone production Cushing syndrome –most common endocrinopathy 50% with small cell CA of lungs; due to excessive corticotropin production  2. Hypercalcemia Most common paraneoplastic syndrome manifestations. Two processes involved: 1. Osteolysis induced by cancer 2. Production of calcemic humoral substances in extra-osseous neoplasms 3. Acanthosis nigricans Gray-black patches of hyperkeratosis on the skin folds ex. Armpit ,elbow, neck and groin. Thank You