review of neoplasia and immunology of cancer - lecture notes - julia Flashcards
what are the three stages of carcinogenesis?
- initiation - provides genetically altered cells
- promotion - stimulates clonal expansion of intiated cells
- progression - reflects additional genetic and phenotypic changes required for malignancy
what occurs during the promotion stage of carcinogenesis? (what allows for growth?)
- initiated cells are dependent on normal pathways to stimulate growth (clonal expansion)
- exogenous stimuli are substituting for an additional mutation that would confer autonomous control of growth (eg loss of a tumor suppressor gene)
what occurs during the progression stage of carcinogenesis?
- occurs with the stepwise addition of genetic changes/mutations
- confer additional features of the neoplastic phenotype and malignant phenotype
- examples
- angiogenesis
- expression of enzymes that destroy the basement membrane
- expression of telomerase
- evasion of apoptosis
what aspects of inflammation lead to carcinogenesis?
- generation of ROS - nonspecific damagers of proteins and nucleic acids
- increased cell death and turnover => more opportunity for mutations to appear
what inflammatory diseases have been found to be associated with causing cancers? (4)
- ulcerative colitis (autoimmune)
- hepatitis (viral, both B and C)
- chronic pancreatitis (hereditary and other)
- heliobacter pylori, peptic ulcer disease (1% progress to malignancy)
what kind of virus is hep C? (genome? reverse transcriptase?) what are the two hypotheses concerning how it increases risk for hepatocellular carcinoma?
- RNA virus without reverse transcriptase
- nonspecfic hypothesis:
- continuous inflammation and repair => increased cell division and generation of ROS
- specific hypothesis
- proteins transcribed from viral genome in infected cells interact with and inactivate protein products of cellular tumor suppressor genes, thus deregulating control of cell divisions
- true for both hep b and c - can find examples of such viral proteins
what is the evidence that the healthy immune system suppress the development of cancer by rejecting transformed cells? (3)
- transplant patients (immunosuppressed) are known to develop lymphomas and other kinds of cancer
- HIV patients develop Kaposi’s syndrome, non-hodgkins lymphoma, hodgkins disease, and other malignancies
- immune response decreases as you age and many cancers are more prevalent in the elderly
what are the origins of cancer that we’ve discussed? (4 - list)
- inherited or spontaneous mutation
- chemicals (carcinogens)
- radiation
- viruses
what are the characteristics of cancer that we’ve discussed? (5 - list)
- immortal
- invasive
- metastatic
- possess features of normal tissue counterpart from which it derives
- possess unique features different from the tissue from which it derives
what are the ways to prevent cancer? (3)
- avoid carcinogens, radiation, infection
- vaccination (such as for HPV)
- immune surveillance - immune system monitors for abnormal cells
what are some ways to treat cancer? (4)
- surgery
- chemotherapy
- radiation therapy
- immunotherapy
- targeted therapies such as glevec
what are some methods of immunotherapy used to treat cancer? (4)
- cytokines
- antibodies
- vaccination - developing vaccine after tumor is present to train the immune system to attack those cells
- cellular therapies
what is chromothrypsis? how is it different from the normal development of cancer?
- whole chromosome sort of explodes and comes back together
- only a minority of the cases of cancer
- the majority have one change after another that develop over many many years
describe the process of immunoediting (three steps to the presence of cancer)
- at first, the immune system can eliminate the mutated cells (tumor cells blue)
- at some point or in some foci, tumor underges more mutation and an equilibirum is established where the immune system is fighting off the tumor but the tumor is managing to modify itself to avoid destruction
- eventually these cells develop enough mutations that they escape immune survailance and become a tumor
how are NK cells involved in immunosuppresion of tumor?
- have a variety of specific pathways that help them recoginze and eliminate targets
- one potential way to exploit monoclonal antibodies would be to design them to coat tumor cells - the NK cells would then recognize these as targets
- can also recognize cells without class I MHC
- allows destruction of tumor cells that find a way to avoid killing by CD8 cells by turning off MHC production
what are the types of viruses that have been associated with tumors? (RNA virsues, DNA viruses and asssociated tumors)
- RNA
- tuman t-cell lymphotropic virus 1 (HTLV) - adult T cell leukemia/lymhoma
- DNA
- epstein barr - B cell lymphomas including hodgkins lymphoma and nasopharyngeal carcinoma
- human papillomavirus (HPV) - cervical carcinomas
- hepatitis B virus (HBV) - hepatocellular carcinoma
what are some examples of oncofetal antigens that the immune system can identify? (and the type of tumor they’re associated with)
- these are all proteins that are expressed in fetal cells that should not be expressed in the adult
- carcinoembryonic antigen (CEA) - GI, breast cancers
- alpha-fetoprotein (AFP) - hepatomas
what is CEA? how is it used in treatment?
- carcinoembryonic antigen = glycoprotein involved in cell adhesion
- shed from tumor cells - can be detected in blood = good biomarker
- for those patients with high level of cea, remove tumor, and then see if cea levels get high again - this would indicate recurrance
- can also use it to detect micrometasteses in the blood
what can immune cells recognize on cancer cells that would allow for immunosurveilance? (4)
- viruses that cause cancer
- fetal antigens expressed by cancer cells
- mutations expressed by cancer cells
- normal self antigens expressed by cancer cells
what causes autoimmune vitiligo?
- example of autoimmunity in patients who have melanoma that is recognized by the immune system
- patients who develop good immunity also tend to develop vitiligo- eliminate tumor and also develop depigmentation of the skin
- occurs anywhere in the body, not just where the tumor was
- because immune response is against proteins expressed in melanocytes
what are the two ways in which the tumor can hijack the immune system (very general)?
- passive via immune evasion
- active via immune suppression
how do tumor cells evade the immune system?
- t cells recognize and kill antigen-positive tumor cells => growth of tumor cells that don’t express recognizable antigen
- cells with no peptide:MHC ligand, no adhesion molecules, and no co-stimulatory molecules can evade the immune system
how do tumors suppress the immune system?
- they induce regulatory t cells (CD25/CD4 positive cells)
- these then suppress CD8 and CD4 cells
- tumor masses have been found to have a high population of lymphocytes - with current technology, it was recently discovered that these are mostly t reg cells
- tumor cells produce lots of different mediators of the immune system
why is targeting mutations due to chromosome translocation difficult?
- every time you have a chromosome translocation that involves a fusion protein, that fusion region is a new amino acid sequence that has never been seen before by the immune system and that becomes a possible target
- however, this mutated protein is always a little different in every patient - ie the bcr/abl is a bit different in every patient
what would allow a mutation to avoid recognition by the immune system?
- must have the right structure to fit into the class I or class II structure and not every protein has the right structure
what immune factors can tumor cells express? what do each of these factors do? (3)
- many factors that suppress the immune system
- tgf-beta
- IDO (metabolizes arginine that is required for t cells to proliferate)
- iNOS kills t cells
what are myeloid derived repressor cells? (MDSC)
- tumors have lots of myeloid cells
- these have been found to be incredibly immunosuppressive
- tumor cells recruit myeloid cells and convert them to suppressor cells
what cell types form the majority of cells in the tumor?
- only half or less of the mass is actually tumor cells!
- the other 50% consists of stromal cells participating in the development of the tumor in various ways
- these include immune inflammatory cells, cancer-associated fibroblasts, endothielial clels, pericytes
