BMS413 Cancer Biology PDF

BMS413 Cancer Biology Vasiliki Gkretsi, Ph.D  Cancer biology BMS413 The main objective of the Cancer Biology course is to provide a comprehensive overview of the: biology and pathology of cancer signaling mechanisms involved in carcinogenesis the importance of tu...

BMS413 Cancer Biology Vasiliki Gkretsi, Ph.D  Cancer biology BMS413 The main objective of the Cancer Biology course is to provide a comprehensive overview of the: biology and pathology of cancer signaling mechanisms involved in carcinogenesis the importance of tumor microenvironment process of metastasis methods of diagnosis and treatment approaches  Learning outcomes Upon successful completion of this course, students are expected to be able to: Differentiate normal and cancer cells Describe the hallmarks of cancer Describe the main characteristics of common cancer types Explain the types of gene mutations leading to carcinogenesis Define oncogenes and tumor suppressor genes Clarify how cancer cells escape cell death List and describe the steps that lead to metastasis Outline major therapeutic approached against cancer Course outline Office hours!!! Room #116  Contact If you send messages 48h through blackboard, please E-mail: [email protected] rule make sure to click on the “send E-mail” option! EUC policy In case that a student sends email to a faculty member through his/her personal email account please notify them that in order to read the email it must be send through their EUC email account....for any question, clarification or any other issue.  EUC Life Sciences Department Absence policy According to EUC regulations only 3 absences are excused from theory Regardless of whether you are on campus or online!  Make up exams: what, when and why When: there is a SERIOUS reason that can be properly documented within 48h from the date of the exam. Are these considered to be SERIOUS reasons? -medical condition (flu, gastroenteritis, laryngitis, surgery, headache, menstrual cramps…) -accident -poor planning of studying -planned trip/tickets to go to… BMS413 Course evaluation Mid-Term Examination 30% Final Examination 40% Assignments 20% Oral presentation Class participation 10% Total 100% BMS413 grade calculation: Participation 10% Is there a difference between attendance and participation ? Criteria for oral participation ❑ Active contribution to class conversation (without dominating it) ❑ Questions ❑ Well-prepared for the class/lab ❑ Respect for other people’s opinion  Cancer definition Benign & malignant tumors Hallmarks of cancer Vasiliki Gkretsi, Ph.D  Cancer: the definition Cancer includes a variety of pathological conditions that have in common a non-programmed and uncontrolled cell proliferation. Causes: Genetic mutations Environmental exposure to carcinogens or radiation Infections (tumor viruses) Ageing All/some of the above Cancer: known or suspected causes Cancer: known or suspected causes Cancer incidence: geography Cancer classification: anticipated biologic behavior Benign Borderline Malignant unpredictable malignant  Cancer classification: basic histologic types Carcinomas Sarcomas Neuroectodermal Leukemias & -90% of cases -relatively rare tumors Lymphomas -of epithelial origin -of mesenchymal origin -from cells of the CNS or -8% (connective tissue, PNS -liquid tumors (leukemias and muscle, bone) lymphomas)  Cancer: Carcinomas-epithelia-derived cancers Normal Cells are organized similarly, with mature flattened cells at the surface being continually shed and replaced by less differentiated cells that move upward and proceed to differentiate. squamous epithelia of the cervix squamous epithelia of the skin (uterus)  Cancer: Carcinomas-epithelia-derived cancers Abnormal Carcinoma of the esophagus: large tongues of malignant squamous epithelial cells are invading the underlying stromal/mesenchymal tissue. Cancer: Sarcomas-mesenchymal-derived cancers  Cancer: Sarcomas-mesenchymal-derived cancers Rhabdomyosarcomas arise from the cells forming Leiomyosarcoma (arrow, dark purple striated skeletal muscles; the cancer cells (dark nuclei), which arises in cells that form red nuclei) are seen here amid several normal smooth muscle muscle cells (arrows). Cancer: Leukemias and lymphomas  Cancer: Leukemias and lymphomas Normal Abnormal In chronic myelogenous leukemia (CML), a variety of leukemic cells of the myeloid (marrow) lineage are apparent (red nuclei), suggesting the differentiation of myeloid stem cells into several distinct cell types. Types of Leukocytes 1. Neutrophil (40-70%) 2. Eosinophil (1-4%) 3. Basophil (less than 1%) 4. Lymphocytes (20-45%) 5. Monocytes (4-8%)  Cancer: is there anything between normal and abnormal? Between the two extremes of fully normal and highly malignant tissue architectures lies a broad spectrum of tissues of intermediate appearance.  Cancer: a complex multi-step process Hyperplasia: Some growths with cells In these mildly hyperplastic A more advanced hyperplastic that deviate only minimally from those milk ducts, mammary mammary duct shows of normal tissues but may contain epithelial cells have begun epithelial cells that are crowded excessive numbers of cells to form piles that protrude together and almost completely → they appear reasonably normal but into the lumina. fill the lumen. just proliferate too much.  Cancer: a complex multi-step process Metaplasia: Also minimal deviation from normal, where one type of normal cell layer is displaced by Metaplastic conversion of epithelia: the normally cells of another type that are not normally present epithelium is replaced by an epithelium encountered in this site within a tissue. These from a nearby tissue—the process of metaplasia. invaders, although present in the wrong location, i.e. Barrett’s esophagitis, the squamous cells that often appear completely normal under the normally line the wall of the esophagus are microscope. replaced by secretory cells that migrate from the lining of the stomach →precancerous stage  Cancer: a complex multi-step process Dysplasia: Cells within a dysplasia are usually abnormal cytologically. The cytological changes include: variability in nuclear size and shape increased nuclear staining by dyes increased ratio of nuclear versus cytoplasmic size The cells in this dysplasia continue to be densely increased mitotic activity packed (above), in contrast to the more diffuse lack of the cytoplasmic features associated with the distribution of cells in the normal epithelium (left), normally differentiated cells whose cytoplasms (light pink) increase in size as the → Dysplasia is considered to be a transitional state cells differentiate. Numerous mitotic figures are also between completely benign growths and those that are apparent in the dysplasia (white arrows), indicating premalignant. extensive cell proliferation.  Cancer: a complex multi-step process Adenomas, polyps, adenomatous polyps, papillomas, warts (in skin): large growths seen with the naked eye with all cell types found in the normal epithelial tissue that proliferate to form a macroscopic mass. Under the microscope, the tissue looks dysplastic. They grow to a certain size and then stop growing, and they respect the boundary created by the basement membrane, which continues to separate them from the underlying stroma→benign. Adenomatous growths (polyps) in colon and breast tissue  Cancer: a complex multi-step process Cancer or malignant tumors: malignant cells that have a substantial potential of penetrating the basement membrane and infiltrating surrounding tissues Cancer: a complex multi-step process Severity Because more aggressive growths often overgrow their more benign precursors, it is rare to see the multiple states of tumor progression coexisting in close proximity, as is the case in this carcinoma.  Cancer: a complex multi-step process CIS, carcinoma in situ; CIN, cervical intraepithelial neoplasia; DCIS, ductal carcinoma in situ; PIN, prostatic intraepithelial neoplasia.  Summary: Tissue development terms 1. Developmental growth: intended growth of organ structures 2. Reparative growth: tissue repair after an injury 3. Hyperplasia: increase in the number of cells following a signal. The growth stops once the signal is removed. 4. Metaplasia: replacement of one differentiated type of tissue with another following a certain signal 5. Dysplasia or atypical hyperplasia: proliferation of abnormal cells reminiscent of neoplasia 6. Neoplasia: proliferation of abnormal cells that continues even after removal of the signal that initiated it. It is a collection of growths—both benign and malignant. Tumor formation theories Monoclonality versus polyclonality of tumors In a monoclonal tumor: only a single cell is transformed from normal to cancerous behavior to become the ancestor of the cells in a tumor mass. In a polyclonal tumor: multiple cells cross over the border from normalcy to malignancy to become the ancestors of several, genetically distinct subpopulations of cells within a tumor mass. Tumors can be benign or malignant What is the difference? Six (6) Cancer Hallmarks, 2000 1 6 2 5 3 4 Hanahan D, et al. 2000, Cell, Vol.100, 57-70 Ten (10) Cancer Hallmarks, 2011 1 2 10 7 6 3 9 8 5 4 Fourteen (14)Cancer Hallmarks, 2022 Image from AACR Hanahan D. Cancer Discov 2022;12:31–46 doi: 10.1158/2159-8290.CD-21-1059  Tumors can be benign or malignant What is the difference? Cancer Hallmarks Benign tumors Malignant tumors 1. Self sufficiency in growth signals YES YES 2. Insensitivity to anti-growth signals YES YES 3. Apoptosis evasion YES YES YES YES 4. Limitless replicative potential YES YES 5. Sustained angiogenesis 6. Tissue invasion and metastasis NO YES Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000)  Cancer Hallmarks, 2011 Related to proliferation ▪ Sustaining proliferative signaling ▪ Evading growth suppressors ▪ Enabling replicative immortality ▪ Resisting cell death  Cancer Hallmarks, 2011 Related to proliferation ▪ Sustaining proliferative signaling ▪ Evading growth suppressors  Cancer Hallmarks, 2011 Related to proliferation ▪ Enabling replicative immortality  Cancer Hallmarks, 2011 Related to proliferation ▪ Enabling replicative immortality  Cancer Hallmarks, 2011 Related to proliferation ▪ Resisting cell death  Cancer Hallmarks, 2011 Related to immune system ▪ Avoiding immune destruction ▪ Tumor promoting inflammation  Cancer Hallmarks, 2011 Related to immune ▪ Normally T-cells would recognize and kill tumor cells but… system ▪ …Oncogenic signaling promotes PD-L1 (Programmed ▪ Avoiding immune death-ligand 1 ) expression in tumor cells that enables destruction them to escape destruction by T cells. ▪ Inflammation (after an anti-tumor immune response) can ▪ Tumor promoting also induce the expression of PDL1 inflammation  Cancer Hallmarks, 2011 ▪ Inflammation is linked to tumor growth Related to immune (work done by Dr. Rudolf Virchow). system Leukocytes infiltrates were found within ▪ Avoiding immune tumors destruction ▪ Immune cells are present in tumors ▪ Tumor promoting inflammation ▪ Inflammation leads to various hallmarks of cancer as it supplies molecules to the tumor microenvironment, contributing to aberrant tissue repair, proliferation, invasion and metastasis. ▪ Examples….stomach cancer, hepatocellular carcinoma  Cancer Hallmarks, 2011 Related to angiogenesis ▪ Inducing angiogenesis  Cancer Hallmarks, 2011 Related to genetics ▪ Genome instability and mutations -due to chromosomal abnormalities -due to replication errors -due to repair errors -DNA hypomethylation (→high instability and mutation rate) Genetic instability due to…chromosomal abnormalities Normal karyotype 1. Broken chromosomes 2. Multiple copies or pieces of chromosomes 3. Deletions of small pieces or entire chromosomes 4. Translocations 5. All of the above Cancer karyotype Genetic instability due to…chromosomal abnormalities Philadelphia chromosome is the result of a reciprocal translocation between chromosomes 9 and 22 at the locus where the c-abl gene is found in chromosome 9 and the c-bcr gene is found in chromosome 22. The resulting fused chromosome codes for a tyrosine kinase that promotes leukemia formation. Genetic instability due to…chromosomal abnormalities Targeted and effective therapy based on the molecular mechanism! Genetic instability due to…chromosomal abnormalities The successful example of Gleevec! Genetic instability due to…DNA replication errors Normal cell cycle  Genetic instability due to…DNA replication errors Replication errors (a) Errors during spindle formation→ non-disjunction of homologous chromosomes→aneuploidy (b) Errors during DNA replication and repair (c) Errors in the centrosome *Most cancer cells usually bear multiple chromosomal abnormalities Genetic instability due to…DNA replication errors Strategies for detecting and removing the Normal polymerase activity miscopied nucleotides during DNA replication ▪ DNA polymerases are polymerizing in a 5ʹ- to-3ʹ direction ▪ DNA polymerases such as pol-δ look backward performing proofreading (3ʹ-to-5ʹ exonuclease activity) Genetic instability due to…DNA repair errors Normal p53 activity DNA mutations activate the transcription factor p53 which in turn activates the p21 gene. This gene product inhibits the activity of CDK →stops the cell cycle in G1 phase to repair the damage Genetic instability due to…DNA repair errors Mutant p53 In many cancer cells, the p53 gene is mutated and as a result, p21 is not activated →cell cycle continues despite the DNA damage →no repair takes place→damaged DNA is replicated… Genetic instability due to…DNA repair errors In normal cells: Damage in DNA leads to apoptosis →DNA degradation In cancer cells: apoptotic mechanisms are not functional Genetic instability due to…DNA repair errors Normal DNA repair The DNA polymerases, (i.e. pol-δ), occasionally “stutter,” or skip a base when copying a repeating sequence of DNA (e.g., a microsatellite sequence) in the template strand (blue). →the newly synthesized strand (green) either may acquire an extra base that increases the length of the repeating sequence or may lack a base. →Identical dynamics may cause similar changes in microsatellite sequences where the repeat unit is a TC dinucleotide segment. Genetic instability due to…DNA repair errors Normal DNA repair Two components of the Mismatch repair (MMR) apparatus, MutSα and MutLα, collaborate to initiate repair of mismatched DNA. After MutSα scans the DNA and locates a mismatch, MutLα scans the DNA for single-strand nicks, which identify the strand that has recently been synthesized (the recently synthesized strand is under-methylated). MutLα then triggers degradation of this strand back through the detected mismatch, allowing for repair DNA synthesis to follow. Genetic instability due to…DNA repair errors Abnormal DNA repair Defects in the human homolog of MutS play a critical role in triggering hereditary non-polyposis colon cancer (HNPCC). Part of the structure of the T. aquaticus MutS homodimeric protein in complex with a mismatched helix (red) is shown. Genetic instability due to…DNA repair errors Abnormal DNA repair Inherited defects in nucleotide-excision repair, base excision repair, and mismatch repair lead to specific cancer susceptibility syndromes. Example In 1874, Ferdinand Hebra and Moritz Kaposi first characterized the xeroderma pigmentosum (XP) syndrome. XP patients have a 2000-fold increased risk of skin cancer before the age of 20 compared with the general population and about a 100,000-fold increased risk of squamous cell carcinoma of the tip of the tongue. Skin cancers appear in XP children with a median age of ~10 years, compared with ~60 years in the general population. Genes and carcinogenesis…not so simple  Cancer Hallmarks, 2011 Related to energy ▪ Deregulating cellular energetics  Cancer Hallmarks, 2011 Normal cellular respiration ▪ In normal non-proliferating cells having Related to energy access to adequate oxygen, glucose is ▪ Deregulating cellular energetics imported into the cells by glucose (Glucose metabolism) transporters (GLUTs) and then broken down by glycolysis and the citric acid cycle. ▪ During the last step of glycolysis, pyruvate is imported into the mitochondria, where it is oxidized into acetyl CoA for processing in the citric acid cycle. ▪ Altogether, the mitochondria can generate as much as 36 ATP molecules per glucose molecule.  Cancer Hallmarks, 2011 Abnormal cellular respiration ▪ In cancer cells, with/without oxygen, the GLUT1 Related to energy glucose transporter imports large amounts of glucose into the cytosol, where it is processed ▪ Deregulating cellular energetics (Glucose by glycolysis. metabolism) ▪ As the last step of glycolysis, pyruvate kinase M2 (PK-M2) causes its pyruvate product to be diverted to lactate dehydrogenase (LDH-A), yielding lactate that is secreted in abundance by cancer cells. ▪ Little of the initially imported glucose is metabolized by the mitochondria, and as a result as few as 2 ATPs are generated per glucose molecule.  Cancer Hallmarks, 2011 Abnormal cellular respiration Related to energy ▪ Deregulating cellular energetics (Glucose metabolism) Warburg effect paradox: cancer cells switch over from the more efficient energy state to a less efficient one (even in the presence of oxygen)  Cancer Hallmarks, 2011 Abnormal cellular respiration Related to energy ▪ 2-Deoxy-2-(18F )fluoro-glucose positron-emission ▪ Deregulating cellular tomography (FGD-PET) makes it possible to visualize energetics (Glucose tumors in the body that have concentrated large metabolism) amounts of glucose because of the hyperactivity of the GLUT1 transporter in the associated cancer cells. ▪ FDG-PET revealed a small tumor (bright orange; arrow) in the region near an ovary of a woman who was under treatment for breast cancer but was otherwise without symptoms.  Cancer Hallmarks, 2011 Related to metastasis ▪ Promoting invasion and metastasis  Cancer Hallmarks, 2011 Related to metastasis ▪ Metastasis is a complex ▪ Promoting invasion and multistep process during which cancer cells disseminate from metastasis the primary site to a distant site of the body. ▪ It is not as effective as it is generally thought. ▪ In reality there are many obstacles that the cancer cells need to overcome to successfully metastasize. Massague J., et al. Cell 2006 METASTASIS  Cancer Hallmarks, 2022 Related to plasticity Tumorigenesis and malignant progression is facilitated by ▪ Unlocking phenotypic corrupting the normal plasticity differentiation of progenitor cells into mature cells in developmental lineages (3 possible ways). (i) dedifferentiation from mature to progenitor states (ii) blocked (terminal) differentiation from progenitor cell states (iii) transdifferentiation into different cell lineages.  Cancer Hallmarks, 2022 Related to reprogramming ▪ Non-mutational epigenetic reprogramming Gene-regulatory circuits and networks in tumors can be governed by a plethora of corrupted mechanisms that are independent from genome instability and gene mutation.  Cancer Hallmarks, 2022 Related to microbiome ▪ Polymorphic microbiomes Polymorphic microbiomes in one individual versus another (in the colon, other mucosa and connected organs, or in tumors), can diversely influence many of the hallmark capabilities→ tumor phenotype  Cancer Hallmarks, 2022 Related to senescence ▪ Senescent cells Clues are increasingly implicating senescent cell derivatives of many of these cellular constituents of the tumor microenvironment, in modulating hallmark capabilities→ tumor phenotypes. ❑ Terms and definitions ❑ Difference between benign and malignant tumor ❑ Hallmarks of cancer (S.O.S) Non-Neoplastic Proliferation: Hypertrophy – Size Hyperplasia – Number Metaplasia – Change REMEMBER Dysplasia – Disordered Neoplastic Proliferation: Benign: Localized - non-invasive. Malignant:- Spreading, Invasive.