What has been the trend in cancer during the past several decades?
Over the last 50 years of the twentieth century, the overall age-adjusted cancer death rate significantly increased in both men and women.
However, since 1995 the cancer incidence rate in men has stabilized and since 1990 the cancer death rate in men has decreased 18.4%.
In women the cancer incidence rate stabilized in 1995, and the cancer death rate has decreased 10.4% since 1991.
What are the causes of reduction in cancer-related death in male and female in recent years?
Among men nearly 80% of the total decrease in cancer death rates is accounted for by decreases in death rates from lung, prostate, and colorectal cancers since 1990.
Among women nearly 60% of the decrease in cancer death rates is due to reductions in death rates from breast and colorectal cancers.
Nearly 40% of the sex-specific decreases in cancer death rates is accounted for by a reduction in lung cancer deaths in men and breast cancer deaths in women.
What are the causes of decrease in cancer related death?
Decreased use of tobacco products is responsible for the reduction in lung cancer deaths,
Improved detection and treatment are responsible for the decrease in death rates for colorectal, female breast, and prostate cancer
What are the causes of decrease in cancer of stomach and cervix?
Stomach--> a decrease in some dietary carcinogens, as a consequence of better food preservation or changes in dietary habits
between 1990–1991 and 2004, which cancer death rates increased in male and female?
lung cancer death rates in women, and liver and intrahepatic bile duct cancer death rates in men
Number of death from HCC is expected to rise due to...............
large number of individuals infected with the hepatitis C virus (HCV)
......................... had the largest decline in cancer mortality during the past decade.
What is the difference in cancer rates between Hispanics and nonhispanic whites?
Hispanics living in the United States have a lower frequency of the most common tumors than the white non-Hispanic population but a higher incidence of tumors of the stomach, liver, uterine cervix, and gallbladder, as well as certain childhood leukemias.
True or False: The disparity in cancer mortality rates between white and black Americans persists
Axillary lymph node with metastatic breast carcinoma. The subcapsular sinus (top) is distended with tumor cells. Nests of tumor cells have also invaded the subcapsular cortex
True or false: environmental factors are the more significant contributors in most common sporadic cancers
True or False: most overweight individuals in the U.S. population have a higher death rate from cancer than do their slimmer counterparts
Alcohol abuse alone increases the risk of which cancers?
carcinomas of the oropharynx (excluding lip)
by the development of alcoholic cirrhosis, HCC
What are the relation of cancers to smoking?
(bolds also in alcohol)
.................. has been called the single most important environmental factor contributing to premature death in the United States
Alcohol and tobacco together synergistically increase the danger of incurring cancers in the .....................................
upper aerodigestive tract
What are some occupational cancers?
Arsenic and arsenic compounds: Lung, skin, hemangiosarcoma
Asbestos: Lung, mesothelioma; gastrointestinal tract (esophagus, stomach, large intestine)
Benzene: Leukemia, Hodgkin lymphoma
Beryllium and beryllium compounds: Lung
Cadmium and cadmium compounds: Prostate
Chromium compounds: Lung
Nickel compounds: Nose, lung
Radon and its decay products: Lung
Vinyl chloride: Angiosarcoma, liver
................is used for aerospace applications and nuclear reactors
...............Froms from decay of minerals containing uranium
Arsenic can cause:
Lung, skin, hemangiosarcoma
What is the relation of age to cancer?
Cancer is the main cause of death among women aged 40 to 79 and among men aged 60 to 79;
the decline in deathsafter age 80 is due to the lower number of individuals who reach this age
Why increased age is a RF for cancer?
Accumulation of somatic mutations
Decline in immune competence
Neoplasms are the......cause of death in children
What are the mc malignant neoplasms in adults and children?
Children--> acute leukemia and primitive neoplasms of the CNS
What are the three types of inherited cancer syndromes?
INHERITED CANCER SYNDROMES (AUTOSOMAL DOMINANT)
INHERITED AUTOSOMAL RECESSIVE SYNDROMES OF DEFECTIVE DNA REPAIR
What are the AD cancer syndromes?
p53: Li-Fraumeni syndrome (various tumors)
APC: Familial adenomatous polyposis/colon cancer
NF1, NF2: Neurofibromatosis 1 and 2
BRCA1, BRCA2: Breast and ovarian tumors
MEN1, RET: Multiple endocrine neoplasia 1 and 2
MSH2, MLH1, MSH6: HNPCC
PTCH: Nevoid basal cell carcinoma syndrome
PTEN: Cowden syndrome (epithelial cancers)
LKB1: Peutz-Jegher syndrome (epithelial cancers)
What are INHERITED AUTOSOMAL RECESSIVE SYNDROMES OF DEFECTIVE DNA REPAIR?
What are FAMILIAL CANCERS?
What is the genetic of AD cancer syndromes?
The inherited mutation is usually a point mutation occurring in a single allele of a tumor suppressor gene.
The silencing of the second allele occurs in somatic cells, generally as a consequence of deletion or recombination
What are the general features of AD cancer syndromes?
In each syndrome, tumors tend to arise in specific sites and tissues, although they may involve more than one site. There is no increase in predisposition to cancers in general. The one exception to this tumor specific tissue involvement is Li-Fraumeni syndrome.
Tumors within this group are often associated with a specific marker phenotype. For example, there may be multiple benign tumors in the affected tissue, as occurs in familial polyposis of the colon and in MEN. Sometimes, there are abnormalities in tissue that are not the target of transformation (e.g., Lisch nodules and café-au-lait spots in neurofibromatosis type 1)
True or False: There is no increase in predisposition to cancers in general in most AD inherited syndromes of cancer
.....................is the most common cancer predisposition syndrome
Which cancer predisposition syndrome is both due to abnormal repair and AD?
Risk of which cancers are increased in HNPCC?
What are the features of familial cancers?
Features that characterize familial cancers include early age at onset, tumors arising in two or more close relatives of the index case, and sometimes, multiple or bilateral tumors.
Familial cancers are not associated with specific marker phenotypes. For example, in contrast to the familial adenomatous polyp syndrome, familial colonic cancers do not arise in preexisting benign polyps
Segregation analyses of large families usually show that predisposition to the tumors is dominant, but multifactorial inheritance cannot be easily ruled out.
It is likely that familial susceptibility to cancer may depend on multiple low-penetrance alleles, each contributing to only a small increase in the risk of tumor development.
Risk in siblings 2-3 times
What are the links between inflammation and cancer?
Immune response may become maladaptive, promoting tumorigenesis.
Compensatory proliferation is aided by a plethora of bioactive substances produced by activated immune cells that promote cell survival, tissue remodeling, and angiogenesis.
In some cases, chronic inflammation may increase the pool of tissue stem cells, which become subject to the effect of mutagens.
These mediators also cause genomic stress and mutations; additionally the activated immune cells produce reactive oxygen species that are directly genotoxic.
To add insult to injury, many of these mediators promote cell survival, even in the face of genomic damage.
In the short term this can be adaptive. However, in chronic inflammation such behavior is maladaptive, since it allows the creation and fixation of such mutations, eventually leading to cancer.
What are some inflammatory conditions associated with cancer?
In old way of tumor antigen classification, what are tumor associated and tumor specific antigens?
tumor-specific antigens, are present only on tumor cells and not on any normal cells, and tumor-associated antigens, are present on tumor cells and also on some normal cells
.............are the major immune defense mechanism against tumors
What are the groups of tumor antigens?
Products of Mutated Genes
Overexpressed or Aberrantly Expressed Cellular Proteins
Tumor Antigens Produced by Oncogenic Viruses
Altered Cell Surface Glycolipids and Glycoproteins
Cell Type–Specific Differentiation Antigens
What are the features of the products of mutant proteins as tumor antigens?
Can be both expressed via MHCI and II
Because these altered proteins are not present in normal cells, they do not induce self-tolerance.
RAS, p53, and BCR-ABL proteins
These oncoproteins do not seem to be major targets of tumorspecific CTLs in most patients
What is the role of Overexpressed or Aberrantly Expressed Cellular Proteins as tumor antigens?
In a subset of human melanomas some tumor antigens are structurally normal proteins that are produced at low levels in normal cells and overexpressed in tumor cells. Example is tyrosinase that is expressed only in normal melanocytes and melanomas. T cells from melanoma patients recognize peptides derived from tyrosinase. The probable explanation is that tyrosinase is normally produced in such small amounts and in so few cells that it is not recognized by the immune system and fails to induce toleranceAnother group, the “cancer-testis” antigens, are encoded by genes that are silent in all adult tissues except the testis. Although the protein is present in the testis it is not expressed on the cell surface in an antigenic form, because sperm do not express MHC class I antigens. Thus, for all practical purposes these antigens are tumor specific. Prototypic of this group is the melanoma antigen gene (MAGE) family. (GAGE, BAGE, and RAGE)
The most potent of virus encoded tumor antigens are proteins produced by .............................
latent DNA viruses including HPV and EBV
Basis for HPV vaccine
What are the features of Oncofetal Antigens?
Expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues.
Genes encoding these proteins are silenced during development and are derepressed upon malignant transformation.
Their main importance is that they provide markers that aid in tumor diagnosis.
As techniques for detecting these antigens have improved, it has become clear that their expression in adults is not limited to tumors. (inflammation or even normal)
There is no evidence that oncofetal antigens are important inducers or targets of antitumor immunity.
CEA and AFP
What are the Altered Cell Surface Glycolipids and Glycoproteins on the surface of tumor cells?
gangliosides, blood group antigens, and mucins
What are the importance of Altered Cell Surface Glycolipids and Glycoproteins?
Although most of the epitopes recognized by these antibodies are not specifically expressed on tumors, they are present at higher levels on cancer cells than on normal cells.
This class of antigens is a target for cancer therapy with specific antibodies
What are some examples of gangliosides used as tumor antigens?
GM2, GD2, and GD3 in melanoma
What are some clinically important tumor related mucins?
Mucins are high-molecular-weight glycoproteins containing numerous O-linked carbohydrate side chains on a core polypeptide. Tumors often have dysregulated expression of the enzymes that synthesize these carbohydrate side chains, which leads to the appearance of tumor-specific epitopes on the carbohydrate side chains or on the abnormally exposed polypeptide core.
CA-125 and CA-19-9, expressed on ovarian carcinomas, and MUC-1, expressed on breast carcinomas.
Unlike many mucins, MUC-1 is an integral membrane protein that is normally expressed only on the apical surface of breast ductal epithelium, a site that is relatively sequestered from the immune system. In ductal carcinomas of the breast, however, the molecule is expressed in an unpolarized fashion and contains new, tumor-specific carbohydrate and peptide epitopes detectable by mouse monoclonal antibodies.The peptide epitopes induce both antibody and T-cell responses in cancer patients and are therefore being considered as candidates for tumor vaccines
Where is the MUC-1 found and what is its importance?
Unlike many mucins, MUC-1 is an integral membrane protein that is normally expressed only on the apical surface of breast ductal epithelium, a site that is relatively sequestered from the immune system.
In ductal carcinomas of the breast, however, the molecule is expressed in an unpolarized fashion and contains new, tumor-specific carbohydrate and peptide epitopes detectable by mouse monoclonal antibodies. The peptide epitopes induce both antibody and T-cell responses in cancer patients and are therefore being considered as candidates for tumor vaccines
What are Cell Type–Specific (Differentiation Antigens)?
Normally present on the cells of origin
are typically normal self-antigens, and therefore they do not induce immune response in tumor-bearing hosts
Their importance is as potential targets for immunotherapy and for identifying the tissue of origin of tumors
What are some examples of immunotherapy using tumor specific antigens?
Lymphomas may be diagnosed as B cell–derived tumors by the detection of surface markers characteristic of this lineage, such as CD20.
Antibodies against CD20 are also used for tumor immunotherapy. These kill normal B cells as well but because hemopoeitic stem cells are spared, new B cells emerge eventually.
The idiotypic determinants of the surface immunoglobulin of a clonal B-cell population are markers for that B-cell clone, because all other B cells express different idiotypes. Therefore, the immunoglobulin idiotype is a highly specific tumor antigen for B-cell lymphomas and leukemias
True or False: there is no evidence that antibodies play a protective role under physiologic conditions
True or False: administration of monoclonal antibodies against tumor cells can be therapeutically effective
What are the effector mechanisms against tumors?
What is the role of Cytotoxic T lymphocytes in anti tumor defense?
In humans, CD8+ CTLs play a protective role against virus-associated neoplasms (e.g., EBV- and HPV-induced tumors) and have been demonstrated in the blood and tumor infiltrates of cancer patients.
In some cases, such CD8+ T cells do not develop spontaneously in vivo but can be generated by immunization with tumor antigen–pulsed dendritic cells.
What is the role of Natural killer cells in anti tumor defense?
After activation with IL-2 and IL-15, NK cells can lyse a wide range of human tumors, including many that seem to be nonimmunogenic for T cells.
T cells and NK cells seem to provide complementary antitumor mechanisms.
Tumors that fail to express MHC class I antigens cannot be recognized by T cells, but these tumors may trigger NK cells because the latter are inhibited by recognition of normal autologous class I molecules.
The triggering receptors on NK cells are extremely diverse and belong to several gene families. NKG2D proteins expressed on NK cells and some T cells are important activating receptors. They recognize stress-induced antigens that are expressed on tumor cells and cells that have incurred DNA damage and are at risk for neoplastic transformation.
How do Macrophages contribute to anti tumor immunity?
Activated macrophages exhibit cytotoxicity against tumor cells in vitro.
T cells, NK cells, and macrophages may collaborate in antitumor reactivity, because interferon-γ, a cytokine secreted by T cells and NK cells, is a potent activator of macrophages.
Activated macrophages may kill tumors by mechanisms similar to those used to kill microbes (e.g., production of reactive oxygen metabolites ) or by secretion of TNF
What is the mc cancer arise in the setting of immunodeficiency?
Most (but not all) of these neoplasms are lymphomas, often diffuse large B-cell lymphomas
What are the features of XL lymphoproliferative disorder?
X-linked recessive immunodeficiency disorder termed XLP (X-linked lymphoproliferative syndrome), caused by mutations in the gene encoding an adapter protein (SAP), which participates in lymphocyte signaling pathways.
When affected boys develop an EBV infection, such infection does not take the usual self-limited form of infectious mononucleosis but instead evolves into a chronic or sometimes fatal form of infectious mononucleosis or, even worse, B-cell lymphoma
What are the mechanisms of immune evasion by tumors?
Selective outgrowth of antigen-negative variants
Loss or reduced expression of MHC molecules( trigger NK)
Lack of costimulation
Apoptosis of cytotoxic T cells
How dose Lack of costimulation help to tumor evasion?
Sensitization of T cells requires two signals, one by a foreign peptide presented by MHC molecules and the other by costimulatory molecules;
although tumor cells may express peptide antigens with class I molecules, they often do not express costimulatory molecules.
This not only prevents sensitization but also may render T cells anergic or, worse, cause them to undergo apoptosis.
How can we bypass lack of costimulation by tumors?
Immunize patients with autologous tumor cells that have been transfected with the gene for the costimulatory molecule B7-1 (CD 80).
In another approach, autologous dendritic cells expanded in vitro and pulsed with tumor antigens (e.g., MAGE1) are infused into cancer patients. Because dendritic cells express high levels of costimulatory molecules, it is expected that such immunization will stimulate antitumor T cells
How can tumors cause immunosuppression?
Many oncogenic agents (e.g., chemicals and ionizing radiation) suppress host immune responses.
Tumors or tumor products also may be immunosuppressive. For example, TGF-β, secreted in large quantities by many tumors, is a potent immunosuppressant.
In some cases the immune response induced by the tumor may inhibit tumor immunity. For instance, recognition of tumor cells may lead to engagement of the T-cell inhibitory receptor, CTLA4, or activation of regulatory T cells that suppress immune responses
How does antigen masking occur in tumors?
The cell surface antigens of tumors may be hidden, or masked, from the immune system by glycocalyx molecules, such as sialic acid–containing mucopolysaccharides.
This may be a consequence of the fact that tumor cells often express more of these glycocalyx molecules than normal cells do
How can tumor cause apoptosis of T cells?
Some melanomas and hepatocellular carcinomas express FasL. It has been postulated that these tumors kill Fas-expressing T lymphocytes that come in contact with them, thus eliminating tumor-specific T cells
How can immunity promote the tumor growth?
1) activated lymphocytes and macrophages produce growth factors for tumor cells2) regulatory T-cells and certain subtypes of macrophages may suppress the host response to tumors.
3) Enzymes, such as MMPs, that enhance tumor invasion, may also be produced