- Cell and Molecular Basis of Cancer
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- 1.0 Why Take This Course? [I-III]
- .....Why take this course?!?!?
- .....Approx. 83 million Americans living today will get cancer at some time in their lives; one in three; considering family structure this means every persons life is touched by cancer
- .....Annually about half-a-million persons die of cancer; 1,400 daily.
- .....About half of all persons who get cancer are "cured;" Cured means disease-free for 5 years; it is no longer a death sentance; for the first time annual deaths from cancer have declined for two years in a row!
- .....There is significant knowledge available now on ways to prevent (or reduce probability) of getting cancer; new tests are available for early detection
- .....Early detection increases "cure" rates in some types of cancers to 80-100%
- .....However, in a recent study of hundreds of men and women who could test for the presence of BRCA1 gene that raises risk of developing breast, ovarian, or prostate cancer, only 43% wanted to take the test.
- .....NCI estimates cancer cost the nation $104 billion in 1990. That's a significant economic burden in addition to the great emotional burden.
- .....The American Cancer Society was founded in 1913 by ten physicians and five laymen. It now consists of 2 million Americans organized into 3,400 Units. All health volunteers. This course is an ACS "educational outreach" program
- 2.0 Brief Intro to General Characteristics and Causes [V]
- 2.1 Chemicals - Moderate Causative Agent
- Carcinogens and Mutagens
- All carcinogens are mutagens, but not all mutagens are carcinogens
- Ironically, most chemical carcinogens are turned into carcinogens (activated) by cell metabolism
- DNA is the target of carcinogens
- Data on Toxic Chemicals in the Environment
- 2.2 Radiation - Moderate Causative Agent
- We are targets for radiation all our lives; surprizingly natural radiation is a greater threat than man-made radiation in general
- Radiation cause DNA errors which result in cancers or in increased necessity for DNA repair which itself could err; Eg. DNAP I the repair enzyme makes a mistake in repair once in every 100 billion times
- Non-Ionizing and Skin Cancer
- Ionizing and Leukemia
- 2.3 Viral - Infrequent Causative Agent
- DNA Tumor Viruses
- Transform as a result of their replication strategy
- Papovaviruses (eg. SV40 and polyoma) integrate randomly in the host cell and can cause cancer
- Papovaviruses encode two or three proteins that together can transform the host cell
- RNA Tumor Viruses (Retroviruses)
- They are called retroviruses because they must use a special enzyme "reverse transcriptase" to make their RNA genome into DNA for infection
- The resulting DNA is integrated into the host cells DNA and in doing so transduce host cell proto-oncogenes (change them from normal to cancer causing genes)
- EG. Rous sarcoma virus was the first cancer causing virus to be discovered and had a nucleotide sequence called src that was not present in similar but non-transforming viruses but was found in DNA of normal chickens, and finally in many other vertebrates and even invertebrates
- Another type of retrovirus that causes slow transformation of host cells (months rather than days) act by insertion near a proto-oncogene that changes control of that gene by altering the activity of its promoter or enhancer region
- Do Viruses Cause Human Cancers?
- Most cases of viruses causing cancer are found in animal models
- Little definitive evidence exists for specific cases of viruses causing human cancers
- Epstein-Barr viruses has been implicated in Burkitts lymphoma and nasopharyngeal carcinoma
- Hepatitis B virus is correlated with liver cancer
- Papilloma viruses which cause warts appear to be related to some human cervical carcinoma
- 2.4 Human Behavior - Frequent Causative Agent
- Diet
- Smoking
- Sex
- 2.5 Heredity - An Increasingly Suspected Causative Agent
- Implicated in very few cancers
- When people migrate to a new area they exhibit the types of cancers of their new home; wouldn't if cancer was influenced by heredity
- Retinoblastoma case study
- Genetic propensity is another matter; many cancers show an increase in certain families due to the genetics of that lineage; Eg. breast cancer, or lung cancer.
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- 3.0 Steps to Cancer [VI]
- 3.1 Tumor Initiation and Promotion
- . The origin of many cancers seems to follow at least a two-step, process; first they are "initiated" then they are "promoted."
- The two-step origin is an older, but still useful concept: SEE OH.
- Carcinogens are the initiators; promoters act synergistically with initiators; note the relationship between mutagens and carcinogens.
- A promoter is a chemical that may change the normal morphology of a cell type, but not its genes because the cell reverts to normal after removal of the chemical
- A tumor promoter does not by itself result in a cancer; the cells must already have gone thru the initiation stage, which apparently does change the genetics of the cell
- Promoter events must occur after initiation and usually require repeated exposure for weeks to months: SHOW OH ON PROMOTER SERIES
- Cigarette smoke may be thought of as a promoter altho much more specific chemicals have been shown to be.
- 3.2 The Modern Concept of MultiStep Origins of Cancers
- Recall the basic statistics; cancers occur more in older humans; why?
- The "mutation accumulation" theory states that they have been targets longer for both chemical and radiation mutagens and so have suffered more mutations that might alter normal cell shape and behavior.
- Recent research suggests that cancers originate by a multi-hit, multi-step processs, eg. one of several pathways shown to lead to colon cancers is as follows:
- Normal colon; APC gene loss; DNA loses methyl groups; ras gene mutation; DCC gene loss; p53 gene loss; other gene losses?; colon cancer.
- The more we know about each of the steps in origin of a particular cancer, the more possible ways we have to stop the origin of the cancer, or correct it afterwards.
- 3.3 Clonal Selection Theory
- Decades of research seems to indicate that most cancers are composed of cells similar enough to be called "clones"
- A "clone" is a series of genetically identical descendants of one cell; so identical genes and characteristics
- The cancer is a population of cells; as in any population different variants appear over time; some are better at being a cancer than others; one may out compete the others; this is called "clonal selection" or "tumor progression"
- Relevant to cancer treatment; sometimes the cancer that survives a single drug chemotherapy treatment is worse than the original cancer so treat with multiple drugs
- Note the concept here of "selfish" genes and "selfish" cells; cancers are clonal populations of "selfish cells." Normally our somatic cells sacrifice themselves for the survival of our body and transmission of our germ cells (which are identical).
- 3.4 Transformation
- Is the process by which a normal cell becomes a cell that can no longer respond to normal controls over growth and multiplication.
- Transformed cells no longer need "factors" that normal cells need to grow and divide; they grow readily in tissue culture.
- Transformed cells are considered malignant cells because at least 20 or more features of their phenotype have been permanently changed; the change is heritable so they quickly become a population of transformed cells; anti-tissue.
- 3.5 Immortilization
- Refers to the property of some cells to continue to divide without stopping; continuous growth and multiplication
- Does not require other changes in the cell phenotype.
- Cells grown in tissue culture divide for awhile then stop dividing entering a quiescent state; most cells perish during this senescent state called a "crisis."
- For example, mouse cells pass thru "crisis" at ca. 12 generations, while human cells reach "crisis" at ca. 40 generations.
- But some small number of cells survive and become immortal, dividing indefinitely; these are one step along the way to becoming cancerous.
- 3.6 Metastasis
- The tendancy for cancer cells to migrate to sites other than the original and establish secondary cancers at these new sites; the invasion of normal tissue by transformed cells.
- Spread by blood and lymph flows so often in lymph glands near original cancer
- Many cancer cells do not survive passage thru the blood or are successful at establishing a cancer at a new site; est. < 1 in 10,000
- Particular cancers have preferred secondary sites, eg. lung cancer to brain
- Related to the "staging" of a cancer (see below)
- Survival rates decrease rapidly with increased metastasis; most cancer deaths occur due to metastasis
- 3.7 Angiogenesis
- "Angio" refers to blood; so "angiogenesis" means the generation of new blood vessels; all tissues require a good blood supply to survive; even cancers.
- If cancers do not get enough blood (often at their centers), the cancer cells die (necrosis).
- Cancers are abnormal tissues so they do not have a normal blood supply; but they appear to secrete a chemical that causes extensive proliferation of nearby blood vessels to supply them with nutrients thereby robbing the body of needed nutrients and maintaining the tumor.
- In 1971 Folkman proposed that all solid tumors induce the growth of blood vessels by secreting a chemical to cause the body to generate new blood vessels for the cancer; he was ridiculed; later he isolated and prufified molecules that promote angiogenesis; now some 26 companies are working on substances to inhibit angiogenesis in cancers; 8 new drugs are in clinical trials.
- 3.8 Immune Surveillance
- When the body is invaded by strange organisms, (eg. viruses and bacteria), or even foreign proteins (eg. pollen), antibodies made by our immune system attacks them
- Why doesn't it attack cancer cells? Because they're us! Just a little bit altered from us
- Some cancers during their change from normal to transformed cells begin to produce and place TSTA's or tumor specific transplantation antigens on their membranes; these tumor antigens can cause the rejection of such tumors
- But observations of immune deficient individuals (by heredity, organ transplant, or AIDS) shows that the major cancers do not occur in them more frequently; however, rare cancers do occur in them more frequently; so imm. system may save us from some types of cancers
- Then the major cancers must have some way of avoiding our immune surveillance; we don't know how
- Suspect that imm. sensitive cancers are viral caused
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- 4.0 Types of Cancers: Classification [III]
- 4.1 Basic Definition of Cancer
- Tumors or "neoplasms" are characterized by abnormal cell morphology and cell proliferation; it is not the rate of division so much as the lack of feedback controls that characterize cancer.
- Tumors may be "benign" or "malignant."
- Malignant tumors can grow to extensive size at their later stages destroying vital organs and "eating" up the body in the process; they can spread to other tissues far away from the original site.
- Malignant means no longer controlled in time and space and so a threat to the normal organization of the tissues and organs of the body; in the 2nd lecture we will cover the NORMAL process of differentiation in order to understand what is changed in malignant cells; why do cells lose their in-built controls?
- Benign tumors are growths that have lost the capacity to develop into normal tissues, but are confined to one place; usually encapsulated; not life threatening; they can become very large; one patient came in with a tumor so large it required a wheelbarrow; examples of benign tumors are warts, nevi, etc.
- Benign tumors generally carry the suffix "-oma" alone as in lipoma, or adenoma (benign colon polyp); the status of threat from a cancer is reflected in its name; for example, a chondroma is benign, but a chondrosarcoma is malignant
- 4.2 Carcinomas
- Cancers that occur in cells that form sheets or epithelia that cover tissue surfaces (skin, gut, etc); notice that these are the organs of the body where the most cell proliferation normally occurs anyway.
- Carcinomas are those cancers that arise in endoderm or ectoderm-derived cells.
- More than 90 % of all tumors are in this category
- Carcinomas of the lung, breast, and colon are the most common and fatal in Western countries and account for half of cancer deaths.
- 4.3 Sarcomas
- Cancers that occur in supporting tissues (eg. bones, muscle, blood vessels, fibroblasts).
- Sarcomas are those cancers that arise in mesoderm-derived cells.
- 4.4. Leukemias and Lymphomas
- Cancers of the cells that produce the circulating cells of the blood and immune systems
- Leukemias result in overproduction of leukocytes from the bone marrow
- Lymphomas occur in the lymph nodes and spleen and result in uncontrolled reproduction of lymphocytes
- While carcinomas and sarcomas are most often solid masses, leukemias are not; they grow as individual cells in the blood
- Sarcomas, leukemias and lymphomas account for only 8 percent of all tumors
- 4.5 Over 200 Different Forms of Human Cancer
- Each cell type and pathway to cancer results in a different cancer; many are named for cell type of origin; eg. hepatoma's from liver cells; eg. melanoma from melanin (pigment) producing skin cells
- Some have more generic names; rather than naming the cancer after the specific cell type, they name it after the general type of cell; for example "adenosarcomas", are cancers of glandular (secreting) cells; but an "adenoma" is a benign epithelial tumor with glandular organization; note distinction between chondroma and chondrosarcoma explained above.
- Other exceptions are names which use "blastoma" which refers to embryonic-like tissues or cancers named after their clinician discoverers (eg. Wilm's or Hodgkins)
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- 5.0 Basic Clinical Terms Describing Cancers [V]
- 5.1. General Clinical Terms
- Hypertrophy means "over" "nourish" in terms of increase in cell size without cell division.
- Hyperplasia means "over" "growth" in terms of increase in cell numbers due to increase in frequency of cell division.
- Dysplasia means "abnormal" growth or form" and refers to a change in the size, shape, or organization of cells due to stress as in inflammation in the normal course of healing or in proto-cancers when tissues become initially disorganized.
- Neoplasm simply means "new" "growth" but refers to the unexpected appearance of growth where no normal growth is expected; so we do not call growth of the embryo or wound healing a "neoplasm" because they are expected new growths.
- Biopsy comes from the L. "bio" for "life" and "opsis" for "vision" and refers to the removal of a little piece of a growth to see if it has hypertrophy, hyperplasia, dysplasia, or transformation; in the latter case to see if it is a benign or malignant tumor.
- 5.2. General Concepts of "Level" or "Grading"
- When a patient is biopsied, the tissue is examined histologically under a microscopes with stains to see how far it has progressed from the normal cell morphology; the pathologist also tries to determine its rate of cell division (by counting fraction seen in division)
- Generally the more deviant the morphology, the more malignant the cancer
- 5.3. General Concepts of "Staging"
- Generally refers to how extensive the cancer has spread from its staying in its original site (in situ) (the lowest "stage") all the way to distant metastasis (the highest "stage")
- The further the spread, the higher the stage, the lower the survival rate
- Each clinician or researcher will describe the anatomical structures that are invaded at each "stage" of the cancer progression, usually on a scale of 1 to 5; but these are somewhat different for each cancer because each cancer is in a different anatomical context; rather confusing
- Lately, a more consistent system has been introduced called TNM where T describes the condition of the primary Tumor itself; N describes the extent of lymph node invasion; and M describes the extent of Metastasis
- In the TNM staging scheme, each letter is followed by numbers for the different degrees of involvement, usually 0 to 4 or 5
- Treatment by surgery, or surgery followed by chemo or radiation therapy, or by immunological treatment depends a great deal on the "stage" of the disease
- 6.0 To Understand Cancer, You Must Understand Normal Development
6.1. Totipotency
- A cell that can divide and become any of the specialized cells of the body; complete potential
- Only the recently fertilized egg or early blastomeres are considered totipotent
- Transfer of a terminal cell nucleus to a enucleated egg cytoplasm will sometimes yield a totipotent cell; shows that all genes necessary to develop an adult of the species are present in every cell
- The body has about 1013 cells (10,000 billion) cells all descendents of one, original, lonely, fertilized cell
- 6.2. Terminal Cells
- A cell at the very end of a developmental sequence; it cannot divide any more; it expresses only very highly specialized genes to perform its singular function; then it dies
- Terminal cells have varying but determined lifespans; intestinal cells = few days; red blood cells = 100 days; neural cells, almost your whole life
- 6.3. Differentiation Genes vs. Housekeeping Genes
- As cells divide from each other they become more and more "determined" to become one of the more than 200 specialized cells that make up body organs; this is the basis for embryogenesis of multicellular organisms
- As cells divide they become "different" from each other and gradually lose potency; different genes are turned "on" and "off" in different cell types
- Some important maintenance or "housekeeping" genes are "on" in all cells; these genes are often concerned with important "housekeeping" functions, or normal cell identity, growth, and cell division during embryogenesis
- Most "on" genes are these; but a small number make the cells different for different jobs; both types of genes are involved in cancer if they produce abnormal products
- For example, altho chicken liver and chicken oviduct cells form different organs with different functions, 75 % of their "on" genes are the same; only 5,000 of the 17,000 "on" genes make liver what it is and 3,000 of 15,000 "on" genes make oviduct cells what they are
- A normal mouse liver cell might differ from a normal kidney cell by only 2 or 3000 genes of some 20,000 that are active; therefore only about 10 % of "on" genes might make cells different, with 90 % keeping the cell going as any cell must
- Differentiation is correlated with cell division;
- Control of cell division and cell differentiation is fundamental to the difference in normal and cancer cells
- 6.4. Sequential Subprograms
- Studies of C. elegans, a nematode, whose 1000 somatic cells can be followed from the totipotent egg, through differentiation, to each and every functional body organ, have revealed the exact number and sequence of cell divisions that lead from its larval to adult form; its the same in flies and humans; just more generations of cell divisions & differentiations
- OH of C. elegans: There are many intermediate and temporary "states" of cells that exist only during developmental embryology; these genes are necessary to "hand off" stages or levels of devt to the next stage; and then they are shut off forever; many of these (such as homeotic genes) are common from fruit flies to humans
- So we can distinguish roughly three major categories of genes: Devt type; Housekeeping type; and Diffn type
- It appears at present that cancer cells have mistakes in important housekeeping type genes
- 6.5. Programmed Senescence (Apoptosis): Healthy Death
- Normal cells when taken out of the body and cultured in vitro can only divide 60 to 80 times before dying
- Even if frozen after 30 divisions, unfrozen and cultured, a cell will still only be capable of 30 or so more divisions before it dies; it biochemically remembers
- Some cells are programmed to die on schedule after being produced during development
- Later we will see how one key protein induces death in cells with damaged DNA thereby saving the organ from "bad" cells (cf. p53)
- 6.6. Multiple Levels of Feedback Control
- To accomplish these devt subprograms, cells constantly "ask" each other with biochemicals such questions as, "Who am I"; "Who are you"; "Who are my neighbors"; "Should I divide/die now"; "Which genes should I activate now"
- A flow of feedback signals courses from the outside of the cell at the cell membrane to the inside at the nuclear matrix using the following:
- 1. Membrane Receptors
- 2. Hormones and Growth Factors
- 3. Internal Transducer Relays
- 4. Nuclear Matrix Alterations
- 5. DNA Binding Proteins - Induction and Repressor Proteins
- 6.7. Nature of Embryonic Cell Growth
- 1. Relatively Rapid; More Cell Div. than Death
- 2. Metabolically Intense
- 3. Intensive Cell Movement
- 4. Intensive Signaling
- 5. Sensitive Feedback
- 6. Rigorously Selfless: Respond to Directives
- 7. Sensitive to Timing
- 8. Die on Command & According to Program
- 9. When the Turned-Off Become Turned-On
- Embryo controls should not be
"on" in adults
7.0 New Molecular Discoveries for Understanding Cancer
- 7.1 Proto-Oncogenes
- The normal versions of key developmental control genes are called "proto-oncogenes" because in their normal state they are useful and necessary, but in their altered state they may lead to cancer; this naming convention is an accident of history since their role in carcinogenesis was discovered as the "assay" before their normal role could be detected; thus they are termed "proto" meaning "before" or "first."
- Describe "needle in the haystack" metaphor for the importance of this discovery and this technique of discovery
- The normal proto-oncogenes are named "C-whatever" because they are from normal cells, the C standing in for "normal Cell"; eg. C-ras, C-src, C-fos
- When the normal housekeeping genes are mutated we call the bad copies "oncogenes" because they are capable of oncogenesis in concert with other cell changes
The Fundamental Pathway for Normal Differentiation; for Transformation; and for Oncogene Classification IS THE SAME
- 1. Growth Factors (Class I Oncs)
- 2. Membrane & Intracellular Receptors (Class II Oncs)
- 3. Intracellular Transducers (Class III Oncs)
- 4. DNA Regulation Proteins (Class IV Oncs)
- 5. Cell Cycle Control Proteins (Class V Oncs)
- Z. Apotosis Control Proteins (New Class of Oncs)
- Transformation Revisited:
- Recall multi-step origin of cancer
- Notice from the above that there are numerous pathways for the origin of any specific cancer
- 7.2 Oncogenes
- Oncogenes are genes that are associated with the development of cancers
- These genes are often bad alterations of normal genes that are concerned with normal cell identity, cell growth, and cell division during embryogenesis;
- Significance first demonstrated ca. 1976 altho first case discovered as early as 1911 with the rous sarcoma virus (however, then the gene level was not understood, just that the virus caused transformation)
- Initially these oncogenes were discovered in viruses that are called "transforming viruses" because they cause normal cells to become cancerous
- Oncogenes in these viruses were found mutated or in altered form in viruses and are placed in wrong positions in the cells of a body upon infection, whereupon instead of acting normally they cause cancer
- Oncogenes are named "V-whatever" because they were first identified in viruses; eg. V-ras; V-src, V-fos; these can also result in carcinogenesis
- When also found in the human genome, these genes are called "H-whatever" such as in H-ras
- H-ras & V-ras is a multigene family of five ras genes
- Mutations that cause ras to cause cancer are usually in position 12 or 61; if the glycine aminoacid in 12 is changed to any other but one ΰ cancer
- Thirty-two C-oncogenes have been found in retroviruses, but more probably exist
- Many oncogenes appear to be genes programmed to be active only during embryonic development and that are supposed to be turned-off during adult life; when reactivated at the wrong time, they cause major trouble; others were good "housekeeping" genes that are altered by mutation and perform uncontrolled versions of their original task
- Act dominantly; only a single copy has to be present, not on both homologous chromosomes
Summary of How Oncogenes Are Activated?
- By Site Mutation that makes its protein product non-functional
- By Site Mutation that makes its upstream control sequence insensitive to its signals, or altered in a way that produces too much or too little product
- By Virus Inserting in a Control Region or Carrying a Piece of or Mutated Human Gene and putting it in the wrong place
- By Chromsomal Translocations & Duplications
- By Chromosomal Deletions
- 7.3 Anti-Oncogenes: Tumor Supressor Genes
- Expt! ...if fuse normal rat cell with cancerous some cell hybrids lose their cancer characteristics ergo normal cells have a gene(s) which turn off cancer
- Expt! ...if compare a particular chromosome across several types of cancers found that one or more regions are always absent because of deletion, ergo genes in that region were suppressing cancer formation
- There are genes whose products suppress tumors; they are the opposite of oncogenes; these are called anti-oncogenes; for cancers to maintain themselves, these must be inactivated.
- Produce proteins that restrain cell proliferation and prevent cells from becoming transformed; called "anti" oncogenes because they stop cancer formation;
- In many of the most frequent cancers (breast, lung, colorectal) these genes are lost or inactivated so their products no longer inhibits tumor formation
- Recall multistep pathway to colon cancer; ((Normal colon; APC gene loss; DNA loses methyl groups; ras gene mutation; DCC gene loss; p53 gene loss; other gene losses?; colon cancer))...
- Normal APC, DCC, and p53 genes serve to suppress tumor formation and their loss occurs in 70% of colon cancers...
- Six specific such genes have been found (eg. p53) but more probably exist...
- Clearly, maintenance of a tumor depends on the presence and absence of different chemicals and gene products, some positive that cause cancer initiation and promotion, some negative which fail to suppress the tumor; we just don't yet know enough about each class for clinical application.
- So tumors are partly maintained by the disabling of suppressors of tumors as well as mutational mistakes to normal genes.
- About a dozen have been identified so far including APC, DCC active in colon carcinoma and RB , and p53 discussed as case studies below
- !!! TREATMENT HOPE: if we introduced a normal TSG into a person who has cancer because of a damaged TSG could cure the cancer; already done in vitro, but not in vivo
- Mini-Case-Study I: p53 gene is on chromosome 17; found to be lost or inactivated in a dozen different types of cancer; it is defective in about 50% of all lung, breast, and colorectal cancers, and these account for about HALF of all cancer deaths.
- Act recessively; mistakes or deletions have to be present on both homologous chromosomes; some like p53 act as dominant negatives
- p53 gene has been found lost or inactivated in a dozen different types of cancer; it is altered and defective in about 50 % of all lung, breast, and colorectal cancers and these account for about half of all cancer deaths
- p53 acts by inducing a radiation damaged cell to die (apoptosis); if we put a normal p53 gene into a cancer cell that is missing both of its p53 copies, the cell dies
- p53 -/- knockout mice embryos develop normally to term but after a few weeks the young mice develop numerous malignant tumors
- OH of p53
- Mini-Case-Study II: Another TSG example is the RB causing retinoblastoma, a rare childhood cancer of the retina of the eye; hereditary
- All persons with retinoblastoma, were found to have a deletion of the same small piece of chromosome
- Mutations to both RB have been found in other tumors such as breast, prostate, and lung; adding a normal RB to these cells reduces their cancer phenotype
- 7.4 Chromosomal Telomeres & Telomerase
- In 1930s B. McClintock & J. Muller discovered "sealants" at the end of chromosomes that stopped them from sticking together; named them "telo" "meres";
- In 1978 Blackburn showed ends of chromosomes had a simple repeating DNA sequence of many Ts & Gs virtually universally; humans eg. are TTAGGG repeated 2,000 times
- Found that ends were dynamic; fluctuate in length between species, cells in a species, and even in the same cell over time; why?
- Led to end-replication problem (Watson); DNA polymerase could not copy all the way to the end of chromosome so chromosomes would shorten with each replication until genes were lost & death
- Enzyme telomerase was discovered; could replicate single-stranded ends of chrs; uniquely possessed short RNA template in addition to protein enzyme; joins chr tip to RNA piece, adds DNA repeat, slides to end of it, and does it again
- But found in late 80s that many normal human terminal cells lack telomerase; also are not immortal; normal to not have telomerase
- Correlated with aging; newborn terminal cells will divide 80-90 times, but 70-year olds only 20-30 times; found that telomere sections got shorter with age and cell divisions; a counter
- Correlated with cancer; in 1994 found active telomerase in 90% of human tumors examined and in none of normal tissues
- Cancer cells appear to have extremely short telomeres because they have survived selection from a larger group that died off as intended; but the survivors activated telomerase at this late stage of decay and these telomerases maintained the short telomeres immortally without death; so cancer
- !!! TREATMENT HOPE; if find drug that stops telomerase could kill cancer cells; but what would it do to the few normal cells that do produce telomerase
- 7.5 Cell Cycle Control Proteins and Cancer
Cyclins
- A family of proteins whose amounts rise and fall across the cell cycle; they combine with cyclin-dependent protein kinases to change the Cdk activity in regulating cell division;
- Protein Kinases
- A kinase is any enzyme that transfers a phosphate group from an ATP to another protein
- Cdks are active only when bound to cyclins
- Phosphorylate specific target proteins to get cell division going
- Genes That Control the Cell Cycle
- Several genes have been discovered that are important to cancer origins and also control the cell cycle, eg. RB, p53, mdm2, Cip1, P16, and cyclinD
- RB appears to control the transition of cells from G1 to S phase because it targets products of the E2F family of genes which are transcription factors that bind to DNA (DRAWING)
- For example, the G1 to S cyclin-dependent kinase phosphorylates RB (recall this is a TSG) and this prevents it from binding E2F setting E2F free to turn on gene expression necessary for G1 to S progress
- 7.6 Growth Factors & Their Receptors
- Proteins that when added to cell cultures causes their proliferation; essentially they are signals, one cells way to activate another cell;
- Can activate several different metabolic responses in their target cells
- Require receptors; other proteins on the cell surface that interact with the growth factors and transfer the "signal" to the rest of the cell; receptors can act thru "signal transducers" at the membrane or diffusible "second messengers"
- If the cell is at the proper setting, interaction with the growth factor will send it into cell division
- Hormones and Epidermal growth factor, EGF, are examples; note EGF would work on epithelial cells as a target
- One natural growth factor has an oncogene named sis; it is like PDGF or platelet derived growth factor; for cells reacting with PDGF, presence of sis causes transformation
- TGF-a is an EGF analogue that is found in many tumor cells and stimulates their cell growth
- Malfunctioning normal cell growth receptors can also cause cancer; they malfunction because they remain active stimulating growth even when they are not receiving their signal a time when they are supposed to be shut off;
- Examples are neu oncogene which because of a change to one code word loses part of the protein & its ability to regulate normally; or erbA oncogene which instead of transferring a stimulus to divide under certain circumstances becomes the always-on stimulus to divide; some of these are when mutated alone do not cause cancer but are a step in the multi-step cancer origin process.
- 7.7 Tumor Necrosis Factors
- Recently three tumor necrosis factors (TNF) have been found and genetically engineered
- Severe bacterial infections cause the body to produce TNF which kills tumor cells preferentially in vitro and in vivo
- Lymphotoxin also kills tumor cells; it has a 30 % sequence homology with TNF;
- a part of TNF is identical to a hormone called Cachectin which also kills cancer cells; why is unknown
- Treatment Hope: With TNF bioengineered have more of it at cheaper cost, so can treat cancers in situ with TNF to kill them.
- List of Characteristic Phenotypic Changes in the Cancer Cell
- This Is An Incomplete List; Not A Sequence; Should be A Network
- Remember: The power of specificity is the power of cure
- Many of the char. listed below are linked, eg. alterations in cytoplasmic matrix alters normal cell migration; alterations in the plasma membrane alters normal cell association and contact inhibition; even the former effects the latter, and so on
- Some of the char. listed below are not linked, eg. immortality is not linked with others; anchorage independence of growth is not linked with cell surface changes in any way we can trace
- If this was an obligate series of steps in a sequence, we would know much more about cancer
- Phenotype: Irregularities in Cell Form or Shape
- Cancer or transformed cells look much different from the normal cell from which they were derived; they are more rounded than normal cells; they produce more ruffles and blebs observed by SEM than normal cells; the cytoplasm is less organized in cross sections in TEM; cells that have defined appearance for their function in particular organs deviate from the normal appearance
- Alterations in Nucleocytoplasmic Ratio
- In general, transformed cells have much larger nuclei relative to their cytoplasm than their normal cell counterparts
- Probably due to extra chromosomes when unfolded in interphase stage of the cell cycle
- Changes in Chromosome Complement: Aneuploidy
- Often cancer cells contain more chromosomes than their normal counterparts; additional chromsomes beyond 46 are maintained in a reproducible fashion; 2N + 1 or 2 etc.
- Sometimes pieces of chromosomes are deleted reproducibly in a transformed cell line
- Clonal Nature of Cancer Cells
- Explain the mosaic nature of the human females (X-chromosome inactivation; Barr bodies; and isozymes from different parents X contribution) which can be used to demonstrate that cancers arise from essentially one cell
- Heterogeneous Character of Cancer Cells
- Since there are many different control sequences that can go awry to induce transformation, and there are many different types of changes that can happen to those many types of control pathways, then even the same type of cancer in the same organ in two different individuals may, in fact, be different cancers caused by different sets of mistakes
- This feature makes treating cancer more difficult
- Loss of Dependence on Anchorage for Growth
- Normal cells will not grow unless firmly attached to a substratum; transformed cells will continue to grow and divide; they form clumps of transformed cells; note how this is related to both metastasis and tumor formation
- Decreased Contact Inhibition of Movement
- Normal cells will stop migration or move in an opposite direction when they come into contact with another similar normal cell; thus they do not overlap; when many meet they form a confluent monolayer, make stable gap junctions on their adjoined membranes, and stop moving entirely; called contact inhibition of movement; transformed cells cannot do this; they form huge piles of cells and continue to move across each other; relate to metastasis and tumor formation
- Changes in Control of Cell Division
- Control of cell division amounts to control of growth and all oncogenes are derived from growth-controlling agents
- Immortality
- Cancer cells are relatively immortal in tissue culture and do not stop