Clinical Features of Neoplasia PDF

Clinical Features of Neoplasia DSPR 139: Neoplasia and Genetics Daria Vasilyeva, DDS  Hallmarks of cancer At a glance - - Self-sufficiency in growth signals - Insensitivity to growth inhibition - Ev...

Clinical Features of Neoplasia DSPR 139: Neoplasia and Genetics Daria Vasilyeva, DDS  Hallmarks of cancer At a glance - - Self-sufficiency in growth signals - Insensitivity to growth inhibition - Evasion of apoptosis - Ability to evade host immune response - Limitless replicative potential (immortality) - Altered cellular metabolism - Sustained angiogenesis - Ability to invade and metastasize - Clinical aspects of neoplasia - Effects of location - Metabolic effects - Hormonal effects - Paraneoplastic syndromes Which of the following is not characteristic of neoplasia? A. Neoplasms are traced back to a single carcinogenic mutation B. Neoplasia occurs independently of physiologic growth signals C. Neoplasms are clonal proliferations D. Neoplasms arise from a single cell  What is neoplasia? Disorder of cell growth triggered by series of genomic alterations - Excessive proliferation is independent of and uncontrolled by physiologic growth signals - Alterations give neoplastic cells survival and growth advantage - Alterations affect a single cell and its clonal progeny - Neoplasms are clonal:neoplastic cells derive from a single mother cell  Carcinogenesis: Recap - Cancer formation is initiated by genetic or epigenetic changes - Carcinogens are agents that cause this damage, thus increasing the risk for cancer, e.g. chemicals, oncogenic viruses, radiation - The damage overcomes repair mechanisms, but is not lethal - Disruption of key regulatory systems allows for tumor promotion (growth) and progression (spread) - Disrupted systems include proto-oncogenes, tumor suppressor genes, regulators of apoptosis, and repair mechanisms  Hallmarks of cancer All cancers show 8 fundamental changes in the physiology of their cells, regardless of specific underlying genetic or epigenetic alterations 1. Self-sufficiency in growth signals 2. Insensitivity to growth inhibition 3. Evasion of apoptosis 4. Ability to evade host immune response 5. Limitless replicative potential (immortality) 6. Altered cellular metabolism 7. Sustained angiogenesis 8. Ability to invade and metastasize  1. Self-sufficiency in growth signals Normal growth factor signaling pathway: – Growth factor binds specific receptor on cell membrane → Transient, limited activation of receptor → Cascading, controlled activation of several cytoplasmic signal-transducing proteins → Transmission of signal to nucleus → Initiation of DNA transcription of specific gene(s) → Changes in gene expression → Expression of factors resulting in cell division Signal transduction pathways can: A. Induce cell division B. Influence gene expression C. Alter cell metabolism D. All of the above Self-sufficiency in growth signaling is a characteristic of mutations in: A. Oncogenes B. Tumor suppressor genes C. Genes that regulate programmed cell death D. Genes involved in DNA repair  1. Self-sufficiency in growth signals Proto-oncogene – Normally functioning gene that participates in signaling pathways Essential for cell growth and differentiation: e.g. growth factors, growth factor receptors, signal transducers, nuclear regulators, cell cycle regulators Oncogene – Proto-oncogene with gain-of-function mutation growth factor oncogenes induce cellular growth growth factor receptor oncogenes mediate signals from growth factors signal transducer oncogenes relay receptor activation to nucleus cell cycle regulator oncogenes mediate progression through cell cycle  1. Self-sufficiency in growth signals Oncogene – Proto-oncogene with gain-of-function mutation – E.g., growth factor oncogene → self-sufficiency of growth Growth-factor signaling pathway becomes constitutive and independent of stimulation by growth factor 2. Insensitivity to growth inhibition Tumor suppressor genes normally apply brakes to cell proliferation Loss-of-function mutations in these genes lead to failure of growth inhibition Example: APC – Encodes protein that normally keeps intracellular levels of β-catenin low – When mutated: β-catenin translocates to nucleus and induces cell cycle progression  3. Evasion of apoptosis Apoptosis – Programmed cell death – Protective cellular response to: Procarcinogenic genomic injury Infection Cancer cannot develop/progress if it doesn’t overcome the ER stress: from metabolic alterations that decrease apoptotic barrier energy stores; genetic mutations in proteins or chaperone proteins, viral infections, chemical insults  3. Evasion of apoptosis Bcl2 normally stabilizes the mitochondrial membrane, blocking release of cytochrome c. Disruption of Bcl2 allows cytochrome c to leave mitochondria and activate apoptosis ER stress: from metabolic alterations that decrease energy stores; genetic mutations in proteins or chaperone proteins, viral infections, chemical insults Which neoplasm overexpresses Bcl-2 and illustrates the survival advantage that cells able to evade apoptosis have? A. Follicular lymphoma B. Follicular dendritic cell sarcoma C. Follicular ameloblastoma D. Follicular thyroid carcinoma  Bcl2 is overexpressed in follicular lymphoma. – t(14;18) moves Bcl2 (chromosome 18) to the Ig heavy chain locus (chromosome 14) → increased Bcl2 Mitochondrial membrane is further stabilized → apoptosis is blocked B-cells, that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center, accumulate → lymphoma.  4. Ability to evade the host immune response Immune surveillance: normal function of the immune system – Constant ‘scanning’ of body and destruction of abnormal cells Cells harboring infectious agents Malignant cells – Performed by: CD8 T lymphocytes Natural killer cells Macrophages  Many cancers express abnormal antigens Mutations → abnormal proteins → expressed on MHC I or have high number of cells undergoing cell death Local macrophages or dendritic cells: Ingest tumor antigens Migrate to local lymph nodes Present antigens to naïve CD8+ T-cells (cytotoxic T cells) Activated, antigen-specific CD8+ T-cells then migrate from LNs to tumor to kill tumor cells 4. Ability to evade the host immune response Immunodeficiency increases risk for cancer Cancers arising in immunocompetent hosts: – Consist of cells that are “invisible” to the immune system -or- – Release factors that suppress host immunity Why are immunodeficiency states associated with increased cancer frequency? A. Increased spontaneous mutation rate of cells in the body B. Altered metabolism of tumor cells C. Pro-carcinogenic inflammatory environment D. Decreased immune surveillance 4. Ability to evade the host immune response Cancer immunoediting – “Natural selection” of cancer cells to avoid immune elimination – Selective outgrowth of antigen-negative variants Reduced or completely lost expression of MHC molecules  Mechanisms by which tumors evade the immune system  4. Ability to evade the host immune response Immune system has normal ‘checkpoint’ pathways in immune response – Prevent overstimulation of immune system Cancer cells can downregulate activity of immune system by activating these checkpoints – May express PD-L1, PD-L2 (programmed death ligands) Activates PD-1 (programmed death-1) receptor on T cells Promotes apoptosis in certain T cells – May activate CTLA-4 receptor on T cells Transmits inhibitory stimulus to activated T cells Questions?  5. Limitless replicative potential (immortality) Most normal cells have capacity to divide 60-70 times – Limited by progressive telomere shortening telomeres shorten with each division → eventually divisions stop  5. Limitless replicative potential (immortality) Maintained telomere length seen in virtually all types of cancer – Usually (85-95%) from up-regulation of telomerase – Normal cells don’t have telomerase Which of the following is NOT true regarding cell replication? A. A normal cell can divide 60-70 times B. Telomeres progressively shorten with each cellular division C. Most human cancers maintain appropriate telomere length via upregulation of telomerase or another mechanism D. Telomerase is typically expressed by normal cells  6. Altered cellular metabolism: the Warburg effect Cells normally generate energy via aerobic respiration (oxidative phosphorylation) – Generates 36 molecules of ATP per molecule of glucose 6. Altered cellular metabolism: the Warburg effect Cancer cells generate energy via aerobic glycolysis: Warburg effect – Generation of 2 molecules of ATP per molecule of glucose – Even in the presence of ample oxygen!! Metabolic pathway similar to anaerobic glycolysis – Generation of 2 molecules of ATP per molecule of glucose – Occurs in cells with limited oxygen supply Why do cancer cells use such an inefficient process?  6. Altered cellular metabolism: the Warburg effect Aerobic glycolysis generates numerous metabolic intermediates – Necessary for synthesis of cellular components Important in frequently dividing cancer cells, which require duplication/synthesis of all cellular components – DNA, RNA, proteins, lipid, organelles… Also important in frequently dividing normal cells, e.g. in embryonic tissues Oxidative phosphorylation does not generate these necessary metabolic intermediates  6. Altered cellular metabolism: oncometabolism Many genetic mutations affect enzymes that participate in Krebs cycle – e.g. mutations in IDH (isocitrate dehydrogenase)  6. Altered cellular metabolism: oncometabolism Many genetic mutations affect enzymes that participate in Krebs cycle – e.g. mutations in IDH (isocitrate dehydrogenase) Mutant IDH catalyzes reaction that produces oncometabolite – Metabolite that enhances carcinogenesis by influencing expression of cancer genes  7. Sustained angiogenesis Like normal tissues, tumors require: – Delivery of oxygen and other nutrients – Removal of waste products Tumors smaller than 1mm3 can receive oxygen and nutrients by diffusion from host vasculature Need to be able to induce angiogenesis to enlarge beyond 1-2 mm3 Conjunctival melanoma  7. Sustained angiogenesis Growing cancers stimulate neoangiogenesis – Process by which new vessels sprout from previously existing capillaries Accomplished by secreting pro-angiogenic cytokines such as VEGF (vascular endothelial growth factor) or FGF (fibroblast growth factor)  7. Sustained angiogenesis Neoangiogenesis has multiple effects on cancer growth – Supply of oxygen, needed nutrients – Secretion of growth factors by endothelial cells Stimulates growth of tumor cells – New vessels are leaky and dilated Simplified access to vascular system for metastasis by tumor cells  8. Ability to invade and metastasize Major cause of cancer-related morbidity and mortality Metastatic process is highly inefficient Circulating tumor cells – < 0.01% of tumor cells entering into circulation develop into metastasis Result of complex interplay between: – Cancer cells – Normal stroma Likely highly controlled by epigenetic mechanisms 1. Epithelial tumor cells are normally attached to one another by cellular adhesion molecules (e.g., E-cadherin) 2. Downregulation of E-cadherin → dissociation of attached cells 3. Cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase/matrix protease 4. Cells attach to fibronectin in the extracellular matrix and spread locally 5. Entrance into vascular or lymphatic spaces allows for metastasis (distant spread)  Before metastasis, tumor cells invade a blood vessel or a lymphatic channel = ‘lymphovascular invasion’  Avenues of metastatic growth Metastasis is preceded/initiated by invasion of vascular system or peripheral nervous system – Lymphovascular invasion Invasion of lymphatic circulation → main route of nodal/regional metastases – characteristic of carcinomas Invasion of vascular circulation → main route of distant metastases – characteristic of sarcomas and some carcinomas – Perineural invasion Some cancers are neurotropic and grow along nerves – Angiotropism: traveling along the outside of blood vessels without entering the bloodstream – Some cancers “seed” body cavities: e.g. ovarian carcinoma in peritoneum Lung metastases identified in 30-55% of all cancer patients  Many cancers first metastasize via lymphatic circulation Cancer cells deposit and grow within regional lymph nodes Perineural invasion Perineural invasion Melanoma angiotropism in mouse model Bentolila LA, et al. Sci Rep. 2016 Apr 6;6:23834  Bloodborne metastasis: vascular dissemination Circulating cancer cells are vulnerable to destruction by several mechanisms – Sheer mechanical stress – Apoptosis [triggered by loss of cell-cell adhesion] – Immune mechanisms [e.g. host lymphocytes] Cancer cells protect themselves by: – Aggregating in clumps – ‘Shielding’ with platelets for protection  Bloodborne metastasis: homing of tumor cells to secondary deposits Tumor cells must adhere to endothelium, egress through basement membrane  The metastatic cascade: homing of tumor cells to secondary deposits Site of distant metastasis depends on: – Anatomic location of primary tumor – Venous drainage of primary tumor Most metastases occur in first location available  The metastatic cascade: homing of tumor cells to secondary deposits Site of distant metastasis is also influenced by: – Tropism of particular tumors for specific tissues For example, prostate carcinoma metastasis has predilection for bone  Cancer metastasis and epithelial-to-mesenchymal transition EMT: epithelial-to-mesenchymal transition – Process of acquisition of mesenchymal phenotype by epithelial cells – Plays a role in tissue development and wound healing – May facilitate acquisition of invasive/metastatic capabilities Associated with expression of certain genes such as SNAIL, TWIST  EMT is presumably followed by ‘MET’ during outgrowth of metastatic tumor Questions?  Clinical features of neoplasia - Benign tumors tend to be slow growing, well circumscribed, distinct, and mobile - Malignant tumors are usually rapid growing, poorly circumscribed, infiltrative, and fixed to surrounding tissues and local structures - Biopsy or excision is generally required before a tumor can be classified as benign or malignant with certainty. - Some benign tumors can grow in a malignant-like fashion, and some malignant tumors can grow in a benign-like fashion Location: Critical determinant of clinical effects (morbidity, mortality) of a tumor  ← Bronchial obstruction by mucoepidermoid carcinoma Lung compression and respiratory failure by mesothelioma →  ← Pathologic fracture of humerus by chondrosarcoma Esophageal rupture from esophageal SCC →  ← Brain herniation from glioblastoma multiforme Hemorrhage following invasion into vessel wall by rectal adenocarcinoma → ← Jaundice in pancreatic carcinoma involving head of pancreas Ventricular compression by cardiac fibromatosis  Cancer cachexia Progressive loss of body fat and lean body mass – Equal loss of lean muscle and fat – Elevated basal metabolic rate – Evidence of systemic inflammation Accompanied by: – Weakness – Anorexia – Anemia Weakness and reduced respiratory function → shortened survival Mechanisms poorly understood Cancer and anemia Infiltrating cancers may provoke a chronic inflammatory reaction Advanced cancer can present with signs and symptoms of extensive inflammation – Hepcidin production increased by IL-6 (and other inflammatory mediators) Decreases iron absorption and transfer to developing erythroid precursors in bone marrow Predisposes to iron-deficiency anemia  Cancer and anemia Advanced cancer can present with signs and symptoms of extensive inflammation – TNFα, IL-1, IFN-γ and other inflammatory mediators: Reduce renal response to anemia – Less erythropoietin produced for given level on anemia Reduce marrow response to erythropoietin – Less erythropoiesis for given level of erythropoietin Hemorrhage, hemolysis also contribute to RBC loss  Cancer and hypercoagulability Increased risk of: – Thrombosis – Embolism – Non-bacterial thrombotic endocarditis Mechanisms include: – Tissue factor production by tumor – Accentuated platelet activation/accumulation – Extrinsic vascular compression and invasion Nonbacterial thrombotic endocarditis in setting of pancreatic adenocarcinoma Hypercalcemia of malignancy Most common metabolic abnormality in the neoplastic setting Most common cause of hypercalcemia – Primary hyperparathyroidism close second Two general mechanisms – Osteolysis caused by cancer growing in bone – Production of calcemic humoral substances by soft tissue neoplasm PTHRP (parathyroid hormone-related protein): related to but distinct from PTH  Hormonal effects of neoplasms Endocrine tumors, benign or malignant, may be functional – Able to synthesize and produce hormones – More typical of benign tumors  Functional pituitary adenomas: somatotroph adenoma Second most frequent type of functional pituitary adenoma Growth hormone-secreting adenoma – Gigantism if appearing in children prior to epiphyseal closure Generalized increase in body size Disproportionately long arms and legs – Variety of other disturbances Diabetes mellitus, hypertension, heart failure  Functional pituitary adenomas: somatotroph adenoma Second most frequent type of functional pituitary adenoma Growth hormone-secreting adenoma – Acromegaly if appearing after epiphyseal closure Enlargement of bones of face, hands, feet – Mandibular enlargement: prognathism Continued growth of skin: coarse skin Enlarged visceral organs – Thyroid, heart, liver, adrenals – Variety of other disturbances Diabetes mellitus, hypertension, heart failure  Paraneoplastic syndromes Disease ‘next to’ neoplasm – Caused by or resulting from presence of neoplasm in body – Not due to physical presence of tumor in organ affected Occur in approximately 10% of cancer patients – May be earliest manifestation of occult (hidden) neoplasm – May mimic metastatic disease and confound treatment – May cause significant clinical problems Macroglossia from amyloid deposition in multiple myeloma and even fatality  ← Hemorrhagic stroke in setting of pheochromocytoma-induced hypertension Paraneoplastic autoimmune multiorgan syndrome in setting of lymphoma/leukemia →  Leser-Trelat sign (rapid appearance of multiple seborrheic keratoses), usually in association with gastric adenocarcinoma Which of the following is NOT a potential effect of cancer on the host? A. Anemia B. Hypocoagulability C. Hypercalcemia D. Paraneoplastic syndromes