8/24/2011

What is cancer?
An unnatural and uncontrolled proliferation of cells. Usually originates from the uninhibited growth of mutated cells. Immunologically, cancer cells can be viewed as altered selfg y, cells that have escaped normal growth-regulating mechanisms. What is the molecular basis of cancer? Mutations in genes result in altered proteins During cell division E t External agents l t Random event Most cancers result from mutations in somatic cells Some cancers are caused by mutations in germline cells

1. DNA of a normal cell

Thi piece of DNA i an exact copy of th DNA f This i f is t f the from which it came. When the parent cell divided to create two cells, the cell's DNA also divided, creating two identical copies of the original DNA.
www.cancer.gov

8/24/2011

2. Mutation of DNA

Here is the same section of DNA but from another cell. If you can imagine that DNA is a twisted ladder, then each rung of the ladder is a pair of joined molecules, or a base pair. With this section of DNA, one of the base pairs is different from the original. This DNA has suffered a mutation, either through mis-copying (when its parent cell divided), or through the damaging effects of exposure to radiation or a chemical carcinogen.
www.cancer.gov

3. Genetically altered cell

Body cells replicate through mitosis, they respond to their surrounding cells and replicate only to replace other cells. Sometimes a genetic mutation will cause a cell and its descendants to reproduce even though replacement cells are not needed needed. The DNA of the cell highlighted above has a mutation that causes the cell to replicate even though this tissue doesn't need replacement cells at this time or at this place.
www.cancer.gov

8/24/2011

4. Spread and second mutation

The genetically altered cells have, over time, reproduced unchecked, crowding out the surrounding normal cells. The growth may contain one million cells and be the size of a pinhead. At this point the cells continue to look the same as the surrounding healthy cells. After about a million divisions, there's a good chance that one of the new cells will have mutated further. This cell, now carrying two mutant genes, could have an altered appearance and be even more prone to reproduce unchecked.
www.cancer.gov

5. Third mutation

Not all mutations that lead to cancerous cells result in the cells reproducing at a faster, more uncontrolled rate. For example, a mutation may simply cause a cell to keep from self-destructing. All normal cells have surveillance mechanisms that look for damage or for problems with their own control systems. If such g y problems are found, the cell destroys itself. Over time and after many cell divisions, a third mutation may arise. If the mutation gives the cell some further advantage, that cell will grow more vigorously than its predecessors and thus speed up the growth of the tumour.
www.cancer.gov

8/24/2011

6. Fourth mutation

The new type of cells grow rapidly, allowing for more opportunities for mutations. The next mutation paves the way for the development of p y p an even more aggressive cancer. At this point the tumour is still contained.
www.cancer.gov

7. Breaking through the membrane

The newer, wilder cells created by another mutation are able to push their way through the epithelial tissue's basement membrane, which is a meshwork of protein that normally creates a barrier The invasive cells in this barrier. tumour are no longer contained. At this point the cancer is still too small to be detected.
www.cancer.gov

8/24/2011

8. Angiogenesis

Often during the development of earlier stages of the tumour, or perhaps by the time the tumour has broken through the basement membrane (as pictured above), angiogenesis takes place. Angiogenesis is the recruitment of blood vessels from the network of neighbouring vessels vessels. Without blood and the nutrients it carries, a tumour would be unable to continue growing. With the new blood supply, however, the growth of the tumour accelerates; it soon contains thousand million cells and, now the size of a small grape, is large enough to be detected as a lump
www.cancer.gov

9.Invasion and dispersal

The tumour has now invaded the tissue beyond the basement membrane. Individual cells from the tumour enter into the network of newly formed blood vessels, using these vessels as highways by which they can move to other parts of the body. A tumour as small as a gram can send out a million tumour cells into blood vessels a day.
www.cancer.gov

8/24/2011

11. Metastasis

To form a secondary tumour, a tumour cell needs to leave the vessel system and invade tissue. The cell must y attach itself to a vessel's wall. Once this is done, it can work its way through the vessel and enter the tissue. Although perhaps less than one in 10,000 tumour cells will survive long enough to establish a new tumour site, a few survivors can escape and initiate new colonies of the cancer. www.cancer.gov

Types of cancer
Cancers are classified by the type of cell that the tumor resembles and is therefore presumed to be the origin of the tumor. These types include: Carcinoma: Cancers derived from epithelial cells. This group includes many of the most common cancers, particularly in the aged, and include nearly all those developing in the breast, prostate, lung, pancreas, and colon. S Sarcoma: C Cancers arising f i i from connective ti ti tissue (i.e. bone, cartilage, fat, nerve), each of which develop from cells originating in mesenchymal cells outside the bone marrow.

8/24/2011

Lymphoma and leukemia: These two classes of cancer arise from hematopoietic (blood-forming) cells that leave the marrow and tend to mature in the lymph nodes and blood, respectively. Germ cell tumor: Cancers derived from pluripotent cells, most often presenting in the testicle or the ovary (seminoma and dysgerminoma, respectively dysgerminoma respectively. Blastoma: Cancers derived from immature "precursor" cells or embryonic tissue. These are also commonest in children

Common Cancer Types

Prostate Cancer Thyroid Cancer Cervical Cancer Lung Cancer Breast cancer Leukemia

Cancer cells (Breast)

Cancer cells (Brain)

8/24/2011

Properties of cancer cells

1) Cancer cells show uncontrolled mitotic divisions causing unorganised growth 2) Due to uncontrolled growth and division of cells, a tumour (also called Neoplasm is generally formed) 3) Cancer cells are far less adhesive than the normal cells so they cells, generally wander through the tissues to cause cancerous growth in different parts of the body. This ability of cancer cells to invade new sites is termed as Metastasis. 4) They have decreased requirements for growth factors and serum. 5) They are no longer anchorage-dependent. 6) They grow in a density-independent fashion. 7) Cancer cells and transformed cells can be subcultured indefinitely; that is, for all practical purposes, they are immortal. 8) Cancer cells exhibit a number of alterations on cell surface, in the cytoplasm and in their genes. 9) Cancer cells do not undergo differentiation.

8/24/2011

Oncogene: An oncogene is a gene that when mutated or expressed at abnormally-high levels contributes to converting a normal cell into a cancer cell. Oncogenes disrupted a cells ability to control its own growth and DNA repair mechanisms. Normally mitosis (cell division) is a carefully regulated event, requiring the activation of one protein to activate another, in what is known as a signal transduction cascade. This cascade eventually culminates in changes in gene expression that prepares the cell for mitotic g g p p p events. Oncogenes are mutated forms of proto-oncogenes; these genes are often involved in growth signalling and anti-apoptotic pathways. When proto-oncogenes mutate to become oncogenes they retain their functionality, but are no longer capable of responding to normal regulatory signals.

8/24/2011

Conversion of proto-oncogenes into oncogenes can involve mutation, resulting in production of qualitatively different gene products, or DNA amplification or translocation, resulting in increased or decreased expression of gene products.

10

8/24/2011

How does a proto-oncogene become an oncogene? (Cause)

An oncogene can be the result of several different types of DNA alterations. These fall into two broad categores: 1. Point mutations 2. Chromosomal rearrangements. Point mutation refers to the substitution of one base for another, resulting in a change in that particular amino acid. Chromosomal rearrangements involve whole pieces of chromosomes breaking off and fusing with other chromosomal fragments. Both of these events can result in either altered activity or intracellular levels of the protein

What happens when proto-oncogene become an oncogene ? Consequence

A mutation within a proto-oncogene can cause a change in the protein structure, causing an increase in protein (enzyme) activity a loss of regulation g An increase in protein concentration, caused by an increase of protein expression (through misregulation) an increase of protein (mRNA) stability, prolonging its existence and thus its activity in the cell a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell A chromosomal translocation (another type of chromosome abnormality), causing an increased gene expression in the wrong cell type or at wrong times the expression of a constitutively active hybrid protein. This type of aberration in a dividing stem cell in the bone marrow leads to adult leukemia

11

8/24/2011

Tumor suppressor gene

Tumor suppressor genes, or anti-oncogenesencodes proteins that inhibit excessive cell proliferation. Inactivation of these results in unregulated proliferation E Examples: retinoblastoma gene (Rb) p53 etc l i bl (Rb), 53 p53 (also known as protein 53 or tumor protein 53), is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer. As such, p53 has been described as "the guardian of the genome", the "guardian angel gene", and the "master watchman", referring to its role in conserving stability by preventing genome mutation

12

8/24/2011

p53 has many mechanisms of anticancer function, and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms: It can activate DNA repair proteins when DNA has sustained damage. It can induce growth arrest by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the th DNA repair proteins will have time to fix the i t i ill h ti t fi th damage and the cell will be allowed to continue the cell cycle). It can initiate apoptosis, the programmed cell death, if DNA damage proves to be irreparable.

p53 pathway: In a normal cell p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. complex Once activated p53 will induce a cell activated, cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown. Activated p53 binds DNA and activates expression of several genes including WAF1/CIP1 encoding for p21. p21 (WAF1) binds to the G1S/CDK (CDK2) and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity.

13

8/24/2011

When p21(WAF1) is complexed with CDK2 the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective 3 ff way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Thus, cells will divide uncontrollably, and form tumors

Xeroderma Pigmentosum
This rare disorder is caused by a defect in the gene that encodes a DNA-repair enzyme called UV-specific endonuclease. Individuals with this disease are unable to repair UV-induced mutations and consequently develop skin cancers. cancers

14

8/24/2011

15

8/24/2011

16

8/24/2011

17

8/24/2011

Telomere, telomerase and cancer A telomere is a region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from deterioration. The telomere regions deter the degradation of genes near the ends of chromosomes by allowing for the shortening of chromosome ends, which necessarily occurs during chromosome replication. As a cell begins to become cancerous, it divides g more often and its telomeres become very short. If its telomeres get too short, the cell may die. It can escape this fate by up-regulating an enzyme called telomerase, which can prevent telomeres from getting shorter and even elongate them.

Cancer cells require a mechanism to maintain their telomeric DNA in order to continue dividing indefinitely (immortalization). A mechanism for telomere elongation or maintenance is one of the key steps in cellular immortalization and can be used as a diagnostic marker in the clinic. Telomerase, the enzyme complex responsible for elongating telomeres, is activated in approximately 90% of tumors.

18

8/24/2011

19

8/24/2011

DNA and RNA viruses

A number of DNA and RNA viruses have been shown to induce malignant transformation. transformation Two of the best-studied are SV40 and polyoma. In both cases the viral genomes, which integrate randomly into the host chromosomal DNA, include several genes that are expressed early in the course of viral replication. SV40 encodes t f i l li ti d two early l proteins called large T and little T, and polyoma encodes three early proteins called large T, middle T, and little T.

20

8/24/2011

Retroviruses
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to p p y produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the h t ll' DNA th host cell's DNA. Retroviruses are enveloped viruses that belong to the viral family Retroviridae.

The order of steps from a retroviral gene to a retroviral protein is: RNA DNA RNA protein. Retroviruses that cause tumor growth include Rous sarcoma virus and mouse mammary tumor virus. Cancer can be triggered by proto-oncogenes that were mistakenly incorporated into proviral DNA or by the disruption of cellular proto-oncogenes.

21

8/24/2011

Rous sarcoma virus contains the src gene that triggers tumor formation. Later it was found that a similar gene in cells is involved in cell signaling which was most signaling, likely excised with the proviral DNA. Nontransforming viruses can randomly insert their DNA into proto-oncogenes, disrupting the expression of proteins that regulate the cell cycle. The promoter of the provirus DNA can also cause over expression of regulatory genes.

Polyomavirus It belongs to the family Polyomaviridae. Polyomaviruses have been extensively studied as tumor viruses in humans and animals The tumor suppressor molecule p53 was e tu o supp esso o ecu e as discovered, for example, as a cellular protein bound by the major oncoprotein (cancercausing protein) T antigen made by SV40.

22

8/24/2011

Polyomaviruses are DNA-based (doublestranded DNA, ~5000 base pairs, circular genome), small (40-50 nanometers in diameter), and icosahedral in shape, and do not have a lipoprotein envelope envelope. They are potentially oncogenic (tumorcausing); they often persist as latent infections in a host without causing disease, but may produce tumors in a host of a y p different species, or a host with an ineffective immune system. The name polyoma refers to the viruses' ability to produce multiple (poly-) tumors (-oma).

SV 40 virus
SV40 is an abbreviation for Simian vacuolating virus 40 or Simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors, p , but most often persists as a latent infection.

23

8/24/2011

SV40 is believed to suppress the transcriptional properties of the tumorsuppressing p53 in humans through the SV40 Large T-antigen and SV40 Small TT antigen T antigen. p53 is responsible for initiating regulated cell death ("apoptosis"), or cell cycle arrest when a cell is damaged. A mutated p53 gene may contribute to uncontrolled cellular proliferation, leading to a tumor.

Papillomaviruses
Papillomaviridae is an ancient taxonomic family of non-enveloped DNA viruses, y p p collectively known as papillomaviruses. Infection by most papillomavirus types, depending on the type, is either asymptomatic or causes small benign tumors, known as papillomas or warts. They are highly host- and tissue-tropic, and are rarely transmitted between species.

24

8/24/2011

Papillomaviruses replicate exclusively in the basal layer of the body surface tissues. All known papillomavirus types infect a particular body surface, typically the skin or mucosal epithelium of the genitals, anus, mouth, or airways. Papillomas caused by some types, however, such as human papillomaviruses 16 and 18, carry a risk of becoming cancerous.

Hepatitis B virus (HBV)

The genome of HBV is made of circular DNA, but it is unusual because the DNA is not fully double-stranded. One end of the full length strand is linked to the viral DNA polymerase.
Hepatitis B virus is a member of the Hepadnavirus family. The virus particle, (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein.

25

8/24/2011

Hepatitis B is one of a few known nonretroviral viruses which use reverse transcription as a part of its replication p process. In addition to causing hepatitis B, infection with HBV can lead to cirrhosis and hepatocellular carcinoma. It has also been suggested that it may increase the risk of pancreatic cancer.

Hepatitis C virus (HCV)

HCV is a small (55-65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae Flaviviridae. The hepatitis C virus particle consists of a core of genetic material (RNA), surrounded by an icosahedral protective shell of protein, and further encased in a lipid (fatty) envelope of cellular origin. Two viral envelope glycoproteins, E1 and E2, are embedded in the lipid envelope. Chronic exposure of HCV causes liver cancer.

26

8/24/2011

Adenovirus
Adenoviruses are medium-sized (90100 nm), nonenveloped (without an outer lipid bilayer) icosahedral viruses composed of a nucleocapsid and a double-stranded linear DNA genome. Adenoviruses represent the largest nonenveloped viruses. Adenoviruses are able to replicate in the nucleus of mammalian cells using the hosts replication machinery.

Adenoviruses do not cause cancer in humans but are instead responsible for colds, colds conjunctivitis and other acute illnesses.

They only become tumorigenic when infected into certain rodent species, such p , as Syrian hamsters.

27

8/24/2011

Methods for the treatment of Cancer

There are four standard methods of treatment for cancer: 1. 2. 3. 4. 4 Surgery Chemotherapy Radiation therapy Immunotherapy and biologic th I th d bi l i therapy

28

8/24/2011

When initially diagnosed with cancer, a cancer specialist, an oncologist, will provide you with the cancer treatment options. options He or she will recommend the best treatment plan based on 1. The type of cancer, 2. How far it has spread, 3. Other factors like the age and general health.

Surgery
Surgery can be used to prevent, treat, stage (determine how advanced the cancer is), and g diagnose cancer. In relation to cancer treatment, surgery is done to remove tumors or as much of the cancerous tissue as possible. It is often performed in conjunction with chemotherapy or radiation therapy.

29

8/24/2011

Chemotherapy
Chemotherapy is a type of cancer treatment that uses of drugs to eliminate cancer cells. Unlike surgery, chemotherapy affects the entire body, not just a specific part. It works by targeting rapidly multiplying cancer cells. Unfortunately, other types of cells in our bodies also multiply at high rates, like hair follicle cells and the cells that line our stomachs. This is why chemo can cause side effects like hair loss and an upset stomach.

Chemotherapy is most commonly given by pill or intravenously (IV), but can be given in other ways. A single type of chemotherapy, or a combination of drugs, may be prescribed for a specific length of time. Like surgery, chemotherapy can be p py prescribed alone, in conjunction with radiation therapy or biologic therapy

30

8/24/2011

Radiation Therapy
Radiation therapy uses certain types of energy to shrink tumors or eliminate cancer cells. cells It works by damaging a cancer cell's cell s DNA, making it unable to multiply. Cancer cells are highly sensitive to radiation and typically die when treated. Nearby healthy cells can be damaged as well, but are resilient and are able to fully recover. Radiation therapy may be given alone, along with chemotherapy, and/or with surgery.

Biological strategies to treat cancer

1. Manipulation of Co-Stimulatory Signals can induce activation of CTL causing tumor destruction

31

8/24/2011

2. Transfection of tumor cells with the gene encoding GM-CSF allows the tumor cells to secrete high levels of GM-CSF. This cytokine will activate dendritic cells in the vicinity of the tumor, enabling the dendritic cells to present tumor antigens to both TH cells and CTL-Ps.

3. Cytokine Therapy Can Augment Immune Responses to Tumors

a) Interferons:
All three types of interferon have been shown to increase class I MHC expression on tumor cells. IFN- has also been shown to increase class II MHC expression on macrophages Interferons may act by restoring MHC expression, thereby increasing CTL activity against tumors

b) Tumor Necrosis factors: )

In the presence of TNF- or TNF-, a tumor undergoes visible hemorrhagic necrosis and regression. TNF- has also been shown to inhibit tumor-induced vascularization (angiogenesis by damaging the vascular endothelial cells in the vicinity of a tumor.

32

8/24/2011

4. IN VITROACTIVATED LAK AND TIL CELLS

LAK:
Lymphocytes can be activated against tumor antigens in vitro by culturing them with x-irradiated tumor cells in the presence of IL-2 g and added tumor antigens. LAK-cell populations are typically >90% activated NK cells. However, small numbers of TCR-bearing cells are present in LAK populations and it is possible that these may also contribute to their tumoricidal activity.

TIL:
By taking small biopsy samples of tumors, one can obtain a population of lymphocytes (acting against tumor) and expand it in vitro with IL-2. These activated tumor-infiltrating lymphocytes are called TILs. TILs are of interest because they have increased antitumor activity and require 100-fold lower levels of IL-2 for their activity than LAK cells do.

5. Use of monoclonal antibodies

Anti-idiotype monoclonal antibodies have been used with some success in treating human B-cell lymphomas and T-cell leukemias. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin) used in breast cancer, and the anti-CD20 antibody rituximab, used in a variety of B-cell malignancies.

33

8/24/2011

Guided missile: Monoclonal antibodies to tumor-specific or tumor-associated antigens are coupled with radioactive isotopes, chemotherapy drugs, or potent p py g p toxins of biological origin. Magic bullets: Reagents known as immunotoxins have been constructed by coupling th i hibit chain of a t i ( li the inhibitor h i f toxin (e.g., diphtheria toxin) to an antibody against a tumor-specific or tumor-associated antigen.

34

8/24/2011

6. Hormonal therapy
The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive p tumors include certain types of breast and prostate cancers. Removing or blocking estrogen or testosterone is often an important additional treatment. t t t In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial

7. Angiogenesis Inhibitors
Angiogenesis inhibitors prevent the extensive growth of blood vessels (angiogenesis) that tumors require to survive. Some, bevacizumab, Some such as bevacizumab have been approved and are in clinical use. One of the main problems with anti-angiogenesis drugs is that many factors stimulate blood vessel growth in cells normal or cancerous. Anti-angiogenesis drugs only target one factor, so the other factors continue to stimulate blood vessel growth. Other problems include route of administration, maintenance of stability and activity and targeting at the tumor vasculature.

35

8/24/2011

Source http://www.britannica.com/EBchecked/topic/92230/cancer/224754/ http://en.wikipedia.org/wiki/Cancer http://udel.edu/~swati/ p

36