MOLECULAR BASIS OF CANCER

General Principles -mutation (inherited or acquired), carcinogenesis is a multistep process resulting from accumulation of multiple mutations (an average of 90 mutations) -monoclonal proliferation of cells, initially cancers are monoclonal, at clinical presentation become polyclonal (appearance of aggressive sub- population of cells), which can survive, grow, invade, & metastasize

-targets of genetic damage (normal regulatory genes) -targets of genetic damage (normal regulatory genes) .growth-promoting proto-oncogenes .growth-inhibiting tumor suppressor genes .genes regulating apoptosis .DNA-repair genes

Essential Alterations for Malignant Transformation -self-sufficiency in growth signals -insensitivity to growth-inhibitory signals -evasion of apoptosis -limitless replicative potential -sustained angiogenesis -ability to invade & metastasize -defects in DNA repair

Self-Sufficiency in Growth Signals (autonomous cell proliferation) .mechanism of normal cell proliferation -binding of growth factor to its specific receptor -transient & limited activation of growth factor receptor>activation of signal- transducing proteins on inner leaflet of plasma membrane    -transmission of transduced signal across cytosol to nucleus

-induction & activation of nuclear regulatory factors that initiate DNA transcription    -entry & progression of cell into cell cycle>cell division

Proto-oncogenes, Oncogenes, and Oncoproteins Proto-oncogenes, Oncogenes, and Oncoproteins .proto-oncogenes -are normal genes regulating cellular growth & proliferation -proteins encoded by proto-oncogenes may function as .growth factors .growth factors receptors .signal transducers .transcription factors .cell cycle components

oncogenes -are mutated proto-oncogenes .oncogenes -are mutated proto-oncogenes .oncoproteins -are products of oncogenes -can act as -growth factors -growth factors receptors (tyrosine kinase) -signal transducers (RAC) -transcription factors (MYC) -cell cycle components (cyclins & cyclin-dependent kinases)

Insensitivity to Growth-Inhibitor Signals Insensitivity to Growth-Inhibitor Signals .internal controls of cell cycle (check points-Tumor Suppressor Genes) -sense damage to DNA to prevent cells to complete replication -G1/S checkpoint monitors integrity of DNA before replication (p53-dependent) -G2/M checkpoint checks DNA after replication & monitors safe entry of cells to mitosis (p53-dependent & p53- independent)

-when cells sense DNA damage, checkpoint activation delays cell cycle & triggers DNA repair -if DNA damage is too severe to be repaired, tumor suppressor genes products (RB, p53, APC) lead to .temporary cell cycle arrest (quiescence) .permanent cell cycle arrest (senescence)>apoptosis through growth-inhibitory pathways .cell differentiation

-checkpoint defects that allow cells with damaged DNA to divide, produce mutations in daughter cells that may lead to neoplasia -to function properly, checkpoints require .sensors of DNA damage .signal transducers .effector molecules

.the protein products of tumor suppressor genes may function as -cell surface receptors -signal transduction molecules -transcription factors -cell cycle inhibitors -regulators of cellular responses to DNA damage

Evasion of Apoptosis .in adult, apoptosis is a physiologic response to several pathologic conditions that might contribute to malignancy if cells remained viable .accumulation of neoplastic cells may result from mutations in genes that regulate apoptosis -mutations of component proteins (BCL2-overexpression in follicular lymphoma) -mutation in p53

Limitless Replicative Potential: Telomerase .after fixed number of divisions, normal cells become arrested in non-dividing state achieved by progressive shortening of telomeres at the ends of chromosomes, recognized by DNA repair machinery, & this leads to cell cycle arrest mediated by p53 & RB .in cancers, telomere maintenance results from up-regulation of enzyme telomerase

Angiogenesis .solid tumors cannot enlarge beyond 2mm in diameter unless they are vascularized .functions of neovascularization -effects on tumor growth .supplying nutrients & oxygen .stimulating growth of adjacent tumor cells by secreting growth factors from endothelial cells -providing an access of tumor to metastasis

.angiogenesis is controlled by balance between angiogenesis promoters & inhibitors -promoters, produced by .tumor cells .inflammatory cells (macrophages) .stromal cells .hypoxia (loss of angiogenic inhibitors) -inhibitors .angiostatin .endostatin .vasculostatin

Invasion and Metastases .are biologic hallmarks of malignant tumors .are major cause of cancer-related morbidity & mortality .metastatic cascade has 2 phases -invasion of extracellular matrix -vascular dissemination & homing of tumor cells

Metastatic cascade

invasion of ECM -active process includes several steps .invasion of ECM -active process includes several steps .loosening up of tumor cells .degradation of ECM (proteases, proteases inhibitors) .attachment to ECM proteins .migration of tumor cells, directed by -cytokines, tumor cell-derived -chemotactics, matrix-derived -growth factors, matrix-derived -paracrine effectors, stromal cells- derived

Invasion of epithelial basement membrane

vascular dissemination & homing of tumor cells -within circulation .vascular dissemination & homing of tumor cells -within circulation .tumor cells aggregate in clumps -homotypic adhesions among tumor cells -heterotypic adhesions between tumor cells & blood cells .tumor cells may bind & activate coagulation factors>emboli

-arrest & extravasation of tumor emboli at distant sites involves -arrest & extravasation of tumor emboli at distant sites involves .adhesion to endothelium .migration through BM -at new site, tumor cells .proliferate .develop vascular supply .evade host defenses -tumor cells secrete cytokines, growth factors, & ECM molecules that act on stromal cells, making metastatic site habitable for cancer cells

-site of secondary deposits is related to -site of secondary deposits is related to .anatomic location of primary tumor (first available capillary bed) .endothelial cells of target organs express receptors for adhesion molecules of tumor cells .target organs express receptors for chemokines present in tumors .target organ liberates chemoattractant .target tissue is nonpermissive (unfavorable soil-skeletal muscle)

.theories explaining metastasis -clonal evolution model, tumor cell subclones acquire genetic alterations -metastatic signature .most tumor cells acquire abnormalities that allow them to metastasis -genetic variation (polymorphism), in human population -stem cell hypothesis, metastases require spread of tumor stem cells

Defects in DNA Repair. DNA-repair genes allow mutations in other genes Defects in DNA Repair .DNA-repair genes allow mutations in other genes .examples of diseases with DNA-repair defects -hereditary nonpolyposis colon cancer syndrome (HNPCC) -xeroderma pigmentosum -Bloom syndrome -ataxia telangiectasia -Fanconi anemia

Metabolic Alterations Metabolic Alterations .Warburg Effect -cancer cells shift their glucose metabolism away from mitochondria to glycolysis (aerobic glycolysis) -less efficient glycolysis>decreased demand by tumor cells>increase O2 supply>increase number of tumor cells that can be supported by vessels & increase size of tumor

.Autophagy -under marginal environmental conditions, cancer cells are able to grow without triggering autophagy -under severe nutritional deprivation, cancer cells trigger autophagy> prolonged survival (treatment-resistant)

Chromosomal Changes in Cancers. seen in all types of cancers Chromosomal Changes in Cancers .seen in all types of cancers .are both late phenomenon in cancer progression & initiators of tumor growth .most common -translocation (hematopoietic tumors) -deletion (nonhematopoietic tumors) .important for 3 reasons -therapeutic (identifying oncogenes & tumor suppressor genes) -diagnostic -prognostic

Stromal Microenvironment and Carcinogenesis Stromal Microenvironment and Carcinogenesis .tumor growth & progression depend on -tumor cells (autocrine) -ECM (paracrine-growth & angiogenic factors, cancer cells motility) -immune cells (cytokines-pro- proliferation & pro-survival) -macrophages (promote metastasis) -fibroblasts (desmoplasia-promotes proliferation of tumor cells) potential therapeutic targets

Epigenetic Changes .reversible, heritable changes in gene expression without mutation involving post-translational modifications of histones & DNA methylation .in normal, differentiated cells, majority of the genome is not expressed, some portions are silenced by DNA methylation & histone modifications

.cancer cells have global DNA hypomethylation & selective hyper- methylation .tumor suppressor genes are sometimes silenced by hypermethylation rather than mutation (therapeutic agents to demethylate them) .genomic hypomethylation causes chromosomal instability & may directly contribute to tumor development