癌细胞生物学

2a: Cancer Biology 癌細胞生物學 Clone and clonal evolution 增生中的細胞 蜇伏的細胞 1. Proliferative potential 2. Gives rise to differentiated cells 3. Self renewing Properties of stem cells (幹細胞) Proliferation Differentiation Death Transit Proliferating Exiting Renewing Cellular equilibrium (細胞平衡) Proliferation Differentiation Death Cancer: disruption of cellular equilibrium Post mitoticStem cell Differentiated Normal senescent differentiated cell Benign tumor Grade 2 malignancy Grade 3 or 4 malignancy Sell and Pierce, Lab Invest. 70: 6-22, 1994 Stem cells as the target of carcinogens Anatomy of a cancer: the progression of uterine cervix carcinoma. The dysplasic state appears when neoplastic cells begin to replace the existing epithelium, yet they still divide rather slowly and do not show signs of malignancy. The carcinoma in situ, however, is more dangerous; neoplastic cells have completely replaced the epithelium. Finally, the cells accumulate additional mutations that allow them to break through the basal lamina and invade other tissues. While the dysplasic state often spontaneously regresses, the malignant state does not. Where are stem cells? Note in part F, the brave cell busting through the basal lamina. This is very bad for the individual who has this happening, obviously… …which is why the Pap smear is so important. A represents normal cells, B represents dysplastic cells that are in a variety of differentiated stages, and C represents invasive carcinoma; note the embryonic features of the cells (low nucleus/cytoplasm ratio is pretty classic) Pap smears, unfortunately, are only as good as the people doing and interpreting them, but they represent a good first test to detect neoplasy before it gets worse What is required for Metastasis (轉移)? Must be able to cross the basal lamina (express type IV collagenase) Must not adhere to neighbor cells „ In classic cell culture, cells form a monolayer „ Neoplastic cells continue to grow Must be able to migrate through interstitial fluid and bloodstream to new sites This is, of course, the normal situation, in which cells of epithelia maintain contacts with the basal lamina… …but metastatic cells often express collagenase, allowing them to break down the lamina. In addition, they stop expressing laminin receptors and have cytoskeletal alterations… …that lead to the ability to move past the basal lamina into underlying tissues and eventually the circulatory sytem. Even though a tumor is clonal, all the cells are not alike; they differ in their ability to form metastases, as this experiment clearly demonstrates The cells are picking up additional mutations as they divide, accounting for the phenotypic differences 2b:Molecular Biology of Cancer 癌分子生物學 Oncogenes Tumor suppressor genes Note that cancer results ONLY if the cell is exposed to a tumor promoter repeatedly AFTER an initiator. Note also that multiple initiators may result in cancer (bottom timeline) Cancer onset correlates strongly with age. Sporadic (non-inherited) cancers are rare before 40 years of age, but the risk climbs dramatically after that. On a log-log plot like the one in part B, the relationship looks linear, but it is actually rising roughly as the fifth power. 2-naphthylamine causes bladder cancer, but only does so after several years. The point is that exposure to a carcinogen and the development of cancer can be years apart, pointing out how difficult it is to attach causation to cancers. Shown here is a neoplastic mass among normal cells. The trick used here is to examine which X has been inactivated in the cells by using a marker of some sort. The cells around the mass exhibit random inactivation of one or the other X, while the cells in the mass are all identical. Other markers can be used to definitively demonstrate that tumors are clonal entities. Cancers are clonal; they arise from a single cell that becomes malignant. 癌化過程中什麼基因改變了？ Figure 1 | Example of a protein signalling pathway. Nature Reviews Drug Discovery 1; 683-695 (2002) Clinical proteomics: translating benchside promise into bedside reality Neoplastic proteins/Oncogenes (致癌基因) Growth factors and related hormones serving as ligands for their receptors (EGF, TGF-β, PDGF, etc.) Growth factor receptors (TK receptors, G- linked receptors, Smad receptors, etc.) Intracellular transducers (G- proteins, SH2- SH3 proteins, etc.) Intracellular receptors/transcription factors that realize the ultimate result of the signal Cell-cycle control proteins Newer additions to the menagerie Tumor-suppressor genes (抑癌基因): genes whose products prevent tumor formation; when mutant, tumors result Apoptotic genes (萎凋死亡基因): genes whose products normally induce apoptosis in damaged cells Checkpoint proteins that assess DNA damage in the cell Cancer: General Etiology and PathogenesisCancer: General Etiology and Pathogenesis Cancer Molecular PathwaysCancer Molecular Pathways Downstream effects in presence of ligand Normal Downstream effects in absence of ligand Abnormal Normally, a ligand binds and causes the TK receptor to dimerize, eliciting the downstream effects--- But suppose the N-terminal region is deleted, allowing receptor dimerization whether the signal is there or not---then cells could respond inappropriately to a LACK of signal as if it was there! Other examples include a ligand that binds but does not let go, producing a continuous response…or binding of receptors to the wrong substrate Genetic Mechanisms of TumorsGenetic Mechanisms of Tumors • Gene deletions / amplifications • Mutations • Insertional • Point Mutations • Genetic Instability • Microsatellite Instability (MSI) • Chromosomal Instability (CIN) Genetic Instability in TumorsGenetic Instability in Tumors • Chromosomal Instability • Telomere shortening • Mismatch repair (MMR) genes • Microsatellite Instability Cause and/or tumor progression byproduct ? Progressive Acquisition of Neoplastic Features:Progressive Acquisition of Neoplastic Features: A process of clonal evolutionA process of clonal evolution Hallmarks of Cancer CellsHallmarks of Cancer Cells • Self-maintained replication • Longer survival • Genetic instability • Capable of inducing neoangiogenesis • Capable of invasion and metastasis – Lack of response to inhibitory factors – Self-sustained proliferation Hallmarks of Cancer CellsHallmarks of Cancer Cells • Self-maintained replication • Longer survival • Genetic instability • Capable of inducing neoangiogenesis • Capable of invasion and metastasis – Apoptosis down- regulation – Telomerase reactivation Hallmarks of Cancer CellsHallmarks of Cancer Cells • Self-maintained replication • Longer survival • Genetic instability • Capable of inducing neoangiogenesis • Capable of invasion and metastasis – Mutagenic agents – Cooperative genetic damage – Defective repair systems Hallmarks of Cancer CellsHallmarks of Cancer Cells • Self-maintained replication • Longer survival • Genetic instability • Capable of inducing neoangiogenesis • Capable of invasion and metastasis Basic Biologic Features of Basic Biologic Features of NeoplasmsNeoplasms Oncogenic Lesion (e.g. RAS, MYC, E2F Activation) OncogenicOncogenic LesionLesion (e.g. RAS, MYC, E2F Activation)(e.g. RAS, MYC, E2F Activation) Differentiation Abnormal Proliferation Angiogenesis Invasion SenescenceApoptosis MultistepMultistep TumorigenesisTumorigenesis Sporadic vs. familial cancers Some cancers seem to occur sporadically---that is, with no obvious inheritance pattern These cancers are typically due to mutation events accumulating over the life of the individual (explaining why cancer is typically a disease of older animals) Other cancers strike early and some may seem to be Mendelian traits---these are inherited predispositions What’s the difference? The answer is that early-onset and inherited cancers are situations where one copy of an oncogene is already mutant; only 1 additional hit is required As shown here, there are many ways in which a normal copy of an oncogene could be mutated, and all of these have been observed Basic Mechanisms: Basic Mechanisms: General PathogenesisGeneral Pathogenesis Colon Cancer as a ParadigmColon Cancer as a Paradigm Colon: Anatomy and Function FUNCTION •Storage •Water absorption ANATOMY HISTOLOGY Common Familial Colon Cancer HNPCC FAP FJP/PJS Sporadic Colon Cancer Colon Cancer: Heredity vs. Environment Sporadic Cancer ~65-90% FJP/PJS <0.1% FAP <1% HNPCC 1-2% CFCC 10-30% Adapted from Burt, Gastro, 2000 Colon Adenomas: Pathology Colon Adenocarcinoma Adenoma-Carcinoma Sequence APC/5qLOH K-RAS +7p, +7q, +20q TP53/ -17p -18q, +13q, -4 -8p PRL3 >10 years 5-10 years ~1 year As stated before, numerous changes must occur for metastatic cancer to develop. In colon cancer, it can almost be predicted what the course of gene alteration will be, as is shown by this “timeline” of events. Notice the APC loss at the start and the loss of p53 to produce a carcinoma in situ So even though someone with inherited APC loss has benign polyps, it doesn’t necessarily mean they will become carcinomas…but the chance is much higher Cancer A disease of gene (DNA) Carcinogenesis is a continuous evolutional process. Changes in DNA/genome/RNA/Protein Tumor markers (DNA, RNA, Protein) Early detection is possible Targeting therapy is a feasible goal. 2a: Cancer Biology�癌細胞生物學 What is required for Metastasis (轉移)? 2b:Molecular Biology of Cancer�癌分子生物學 癌化過程中什麼基因改變了？ Neoplastic proteins/Oncogenes (致癌基因) Newer additions to the menagerie Cancer: General Etiology and Pathogenesis Cancer Molecular Pathways Genetic Mechanisms of Tumors Genetic Instability in Tumors Progressive Acquisition of Neoplastic Features:�A process of clonal evolution Hallmarks of Cancer Cells Hallmarks of Cancer Cells Hallmarks of Cancer Cells Hallmarks of Cancer Cells Basic Biologic Features of Neoplasms Sporadic vs. familial cancers Cancer