For the final exam, study CD-ROM quiz questions:

    Ch. 12: 5-12
    Ch. 13: 1-10, 12
    Ch.  14: 1-9
    Ch. 15: 1-12
 

THE DEVELOPMENT AND CAUSES OF CANCER

      Cancer results from loss of the normal regulatory mechanisms that govern cell behaviour

            - much of what we know about normal cell mechanisms comes from identification of
                    the causes of uncontrolled proliferation of cancer cells

            - has to be studied at the molecular and cellular level

Cancer can result from the abnormal proliferation of any type of cell = tumors

            - classified according to the type of cell they arise from

                    e.g. carcinomas = cancers of epithelial cells (90% of human cancers)

                          sarcomas = solid tumors of connective tissues (rare in humans)

                          leukemias = originate from blood-forming cells

                          lymphomas = cancers from cells of the immune system

        Benign tumors - remain confined to their site of origin

                e.g. common skin wart

                - can usually be removed surgically

      Malignant tumors - can invade normal tissues and spread throughout the body

                - only malignant tumors are cancer

        - the four most common cancers (>50% of all cases)
 

Tumors develop from single altered cells that begin to proliferate abnormally

        Additional mutations lead to the selection of cells with progressively increasing capacities
            for proliferation, survival, invasion, and metastasis

              metastasis = the spread of cancer cells through the blood or lymphatic system to
                                            other organ sites

        - multistep process, so most cancers develop late in life

                - abnormalities accumulate over many years

                tumor initiation - genetic alteration leading to abnormal proliferation of a single cell

                tumor progression - additional mutations occur in single cells in tumor population
 

Causes of Cancer:

        Carcinogens = substances that cause cancer

                e.g substances in cigarette smoke, aflatoxin, radiation

                - identified by epidemiological analysis of cancer frequencies, experimental studies
                        in animal models

        Radiation and many chemical carcinogens act by damaging DNA and inducing mutations

                - also called initiating agents because they induce mutations in key target genes that
                        are the first step in cancer development

        Other chemical carcinogens contribute to cancer development by stimulating cell proliferation

                - often called tumor promoters

                - e.g. phorbol esters that stimulate protein kinase C, estrogens

        Viruses also cause cancer

              - viruses cause liver cancer and cervical carcinoma = 10-20% of human cancer worldwide
 

Cancer cells are the result of uncontrolled proliferation

        - exhibit reduced requirements for extracellular growth factors, lack of inhibition by cell-cell contact

              density-dependent inhibition normally restricts proliferation

                - determined in part by availability of growth factors

                - many cancer cells produce growth factors that stimulate their own proliferation (autocrine)
 

many cancer cells also defective in differentiation and/or fail to undergo programmed cell death/apoptosis

        - cells continue dividing by not becoming terminally differentiated

                - other cancer cells are less adhesive than normal

                    e.g. loss of E-cadherin (principal adhesion molecule of epithelial cells) plays large role in carcinomas

        - failure to undergo apoptosis contributes to resistance of cancer cells to radiation and some chemotherapy

                - don't respond   to damaged DNA with cell death

        - cell transformation can convert normal cells into tumor cells that can be studied in cell culture
 

GENES THAT CAN CAUSE CANCER

tumor suppressor = a gene whose inactivation leads to tumor development

        - normally act as brakes that slow down cell cycle progression, inhibit tumor development

                    e.g. Rb, p53, Cdk inhibitors

                    - p53 also required for apoptosis, so inactivation contributes to tumor cell survival

        - SV40 T antigen induces transformation by interacting with cellular Rb and p53 tumor
                suppressor proteins

        - Papillomaviruses induce variety of tumors in animals, e.g. cervical carcinoma in humans

                - transforming proteins interact w/ Rb and p53

        - requires 2 defective copies

oncogene = a gene capable of activating one or more characteristics of cancer cells

        - normally promote cell proliferation

                    e.g. Ras, cyclin D

        - requires only 1 defective copy

        - retroviruses - cause cancer in humans and variety of other animals

                - some contain specific genes responsible for inducing cell transformation

                - many have cellular homologs = oncogenes

      proto-oncogenes = closely-related genes of normal cells - origin of retroviral oncogenes

                        e.g. ras genes are cellular homologs of oncogenes that were first described in retroviruses

                - oncogenes are abnormally expressed or  mutated forms of the corresponding proto-oncogene

                - in human cancers, oncogenes can be activated by point mutations, DNA rearrangements,
                        and gene amplification

        most oncogene proteins function as elements of signaling pathways that stimulate cell proliferation

                - other oncogene proteins interfere w/cell differentiation or apoptosis (e.g. PI 3-kinase, Akt, Bcl-2)
 

Mutations in both oncogenes and tumor suppressor genes contribute to the progressive development
            of cancers

        - accumulated damage to multiple such genes is thought to result in abnormalities in cell proliferation,
            differentiation and survival that are necessary for cancer

            e.g. sequential mutations in APC --> rasK --> MADR2 --> p53
 

Many cancers can be cured if they are detected at early stages of tumor development

        - genetic testing can identify individuals with inherited cancer susceptibilities

                - may allow early detection and more effective treatment of high-risk patients

        - detection of mutations in oncogenes and tumor suppressor genes can also aid in diagnosis and
                monitoring response to treatment

        - drugs targeted against specific oncogenes or tumor suppressor genes can lead to discovery of
                new therapeutic agents that act selectively against cancer cells

                e.g. herceptin that works against certain breast cancers by inhibiting the ErbB-2 receptor tyrosine kinase