Carcinogenesis: The Biology of Cancer PDF

Carcinogenesis The Biology of CANCER Robert Weinberg Ehssan Sharif-Askari [email protected] 1 ABCD of Mole 2  Carcinogenesis Carcinogenesis is the process of malignant transformation – Oncogenesis...

Carcinogenesis The Biology of CANCER Robert Weinberg Ehssan Sharif-Askari [email protected] 1 ABCD of Mole 2  Carcinogenesis Carcinogenesis is the process of malignant transformation – Oncogenesis or tumorigenesis Carcinogens are substances that can induce the process of carcinogenesis Tumor is a mass of cells with uncontrolled cell division Metastasis is the process by which cells from primary tumor migrate to new sites where they form secondary process 3 4  Carcinogenesis-degree of aggressive growth Benign tumors are small and localized tumor that pose little risk to their host. – Pituitary adenomas, induction of acromegaly Malignant tumors are tumors that show evidence of locally invasive and metastatic. 5 6  Cancer During normal development and throughout the life, genetic control system regulate the balance between cell birth and cell death in response to growth signals, and death signals. Cancer is due to failures of these mechanisms that usually control the growth, and cell death within a cell The losses of cellular regulation that give rise to most or all cases of cancer are due to genetic damage that is often accompanied by influence of: – Tumor-promoting chemicals, hormones, and sometimes viruses 7  Onset of cancer Mutation in three set of genes are implicated in the onset of cancer: 1. Proto-oncogenes 2. Tumor suppressor genes 3. Caretaker genes 8  Onset of cancer Proto-oncogenes promote cell growth, once mutated, change to oncogene and cause the gene to be excessively active in growth promotion. Tumor suppressor genes normally restrain growth, so mutations that inactivate them allow inappropriate cell division Caretaker genes normally protect the integrity of the genome, so when inactivated, cells acquired additional mutations at an increased rate, including those that damage growth control and lead to cancer. 9 10  Onset of cancer Cancer results from genetic mutations that arise during a lifetime’s exposure to carcinogens.  Most cancer cells lack one or more DNA repair mechanism (caretaker genes, p53)  The large number of mutations that accumulate  Activate oncogenes  Inactivate tumor-suppressor genes Resulting in uncontrolled proliferation 11 12 13 Question: What type of gene do we have in this picture ??? 14  Onset of cancer Cancer-causing mutations occur mostly in somatic cells and not in germ-line cells. – Germ-line cells: cells that give rise to gametes (sperms and oocytes) and thus participate in formation of next generation of organisms Genetic materials transmitted from one generation to the next – Somatic cells: any cells other than germ cells Genetic material can not be transmitted to the next generation 15  Onset of cancer However, certain inherited mutations, which are carried in the germ lines, increase the probability of cancer formation at one time BRCA1, and BRCA2 (breast caretaker genes) 16  Tumors arise from normal tissue All tissues are composed of cells and cells products, and that all cells arise through the division of pre-existing cells.  Previously, many had portrayed tumors as foreign bodies that had somehow taken root in the body of an affected patient.  Now, tumors, like normal tissues, are composed of masses of cells. Science of Histology 17 18 Types of cancers 19 Classification of cancers 20 Tumor cells arise from many specialized cell types Three primitive cell layers  Ectoderm  Mesoderm  Endoderm 21  Types of cancers Carcinoma Sarcoma Leukemia/lymphoma Neuroectodermal 22  Carcinoma Cancer arise from epithelial cells Responsible for >80% of cancer-related death in the Western world. Include tumors arise from: – GI tract/ mouth, oesophagus, stomach, small and large intestine – Skin/ mammary gland/ pancreas/ lung/ liver/ ovary/ gallbladder/ urinary bladder 23 Tumor cells arise from many specialized cell types The majority of human tumors arise from epithelial tissues Epithelia: Cells that line the walls of cavities and channels or the skin to protect the underneath cells. Why the majority arise from epithelial cells??? 24 Collagen fiber 25  Basement membrane The primary function of the basement membrane is to anchor down the epithelium to its loose connective tissue underneath. The interaction between stromal cells and tumor cells is known to play a major role in cancer growth and progression. Thus, the basement membrane acts as a mechanical barrier, preventing malignant cells from invading the deeper tissues. 26 Collecting tubule-kidney Endometrium of the uterus 27  Types of Carcinoma Epithelial cells that seal the cavity to protect the underlying cell population. ex. skin, nasal cavity, lung,... – Squamous cell carcinoma Some epithelial cells contain specialized cells (gland) that secrete substance into the cavity that they line to protect the epithelial cells from the contents of the cavity. ex. stomach, colon, ovary,... – Adenocarcinoma 28 Adenocarcinoma 29 Renal cell Carcinoma 30 31  Frequent organ sites of carcinoma Lung: Carcinoma comprises >98% of all lung cancers Breast: Nearly all breast cancers are ductal carcinoma Prostate: The most common form of carcinoma of prostate is adenocarcinoma Colon and rectum: Nearly all malignancies of the colon and rectum are either adenocarcinoma or squamous cell carcinoma Pancreas: Pancreatic carcinoma is almost always of the adenocarcinoma type and is highly lethal 32  Basal-cell carcinoma Basal-cell carcinoma is the most common type of skin cancer. It rarely metastaizes or kills. 33  Sarcoma The major class of non-epithelial cancers share a common origin in the mesoderm. These tumor are known as Sarcoma (1%) Include variety mesenchymal cell types: – Fibroblasts, secrete colagen – Adipocytes, store fat – Osteoblasts, form bone – Myocyts, form muscle 34 35 Osteosarcoma 36 Abdominal liposarcoma Fibrosarcoma 37  Leukemia/Lymphoma Cancer derived from hematopoietic cell lineages that moves freely throughout circulation are known as leukemia – Erythrocytes – Plasma cells – B and T cells Lymphomas includes tumors of lymphoid origin (B and T lymphocytes) that aggregate to form solid tumor mass, most frequently in lymph nodes. 38 39 MM ALL NHL 40 41  Neuroectodermal Neuroectodermal tumors arise from cells that forms various components of the central and peripheral nervous system. – Gliomas – Glioblastomas – Neuroblastomas – Schwannomas – Medulloblastomas 42 43  Medulloblastoma Glioblastomas 44  Some Types do not Fit into The Major Classifications Not all tumors fit neatly into one of the four large groups.  Melanomas, derived from melanocytes, arise from embryonic neural crest cells. 45  Cutaneous melanoma with observable metastases. 46 Figure 2.10c The Biology of Cancer (© Garland Science 2007) Melanocytes (arrow) are precursor cells of melanomas 47  Melanomas beginning to move vertically toward the stroma This is a pre-requisite of metastasizing into other tissue 48  Some Types do not Fit into The Major Classifications 1. Small-cell lung carcinomas (SCLCs) contain cells related to neurosecretory cells (secrete biological agents in response to neuronal signaling), such as the adrenal glands derived from neural crest These cells are frequently seen in tobacco users, it is not clear whether they arise from neuroectodermal cells that have insinuated themselves into the lungs or they are endodermal cells that lost their epithelial characteristics. 49  Some Types do not Fit into The Major Classifications/ Trans-differentiation In a small minority of cases, the tumors have shed virtually all of the tissue-specific. These cells are said to have dedifferentiated, and the tumors are anaplastic. No histopathological criteria can be used to identify the tissue from which they have raised 50  Anaplastic tumor with no evident indication of its tissue of origin Attempts to determine the origin with an antibody stain may also prove inconclusive 51  Cancers develop progressively The development of cancer is complex and multi-step process From the two extreme situation: – Normal to severe aggressive cancer, we have a gradual difference in tumor development that each move away from normal to more abnormal tissue. Normal aggressive – Each type of growth represent a distinct step alone cancer 52 development Cancers Develop Progressively What does it mean??? 53 Different Phases of Cancer Development 1 2 3 54 55 56  B A C D 57 Pre-invasive  Cancer progression – 4 steps  Hyperplastic: cancer in which the growth is deviated just minimally from normal tissue, but may contain excessive number of cells. – Metaplasia: cancer with minimal deviation from normal tissues, but cell layer replacement is observed. Metaplasia is usually observed in epithelial transition zones where one type of epithelium meet another one – Between esophagus and stomach  Dysplastic: cells are cytologically abnormal; the appearance of individual cells is no longer normal- nuclear size/increased mitotic activity/ lack of cytoplasmic features... – No invasion to underlying tissue. 58  Cancer progression  Neoplastic: malignant tumors that have substantial potential to invade underlying tissues.  Metastatic: cancer capable of seeding new tumor colonies 59  60 ovarian surface epithelial Cervix squamous cells 61  Barrett’s esophagus Metaplasia 62 Factors affecting cancer formation 63  Cancer formation Factors affecting cancer formation – Heredity Different human populations may carry cancer-susceptibility alleles at great different frequencies - BRCA1, and BRCA2 mutations – Environment Environment in which people live contribute greatly to disease incidence rate that include: air/food/water/lifestyle/dietary choices/ and tobacco usage 64 65  Initial observations: Environmental factors and cancer development 1761, first report connecting between nasal cancer and tobacco snuff Later, lung cancer was documented at high rate with people working in silver mines Exposure to X-ray was associated with lung cancer 1950, evidence for direct link between heavy cigarette smoking and lung cancer was documented (>20X) 66 67 68 Carcinogens 1915, Katsusaburo Yamagiwa: Exposure to chemicals of Coal tar induces 69 tumor formation  Carcinogens 1940, chemist isolated many carcinogens from coal tar These finding clearly stated that several chemical components that entered human body could perturb regular mechanisms within a cell and provoke cancer formation These carcinogenesis can be divided into three categories: – Chemical – Physical 70 – Viral Chemical carcinogens from coal tar 71 72  Carcinogens acts as mutagens 1927, Hermann Muller discovered that he can induces DNA mutation in the genome of Drosophila by exposing them to x-ray Later, other geneticists were able to show that chemical carcinogens can also induce genomic mutations Therefore, the first speculation that cancer is a disease of mutant genes startd to be initiated. 73  Carcinogens acts as mutagens All mutagenic components are likely to be carcinogens 74 How we can find a mutagenic component??? 75  Ames’ test The Ames test is a biological assay to assess the mutagenic potential of chemical compounds 76 77 The End 78