Neoplasia 3- evasion of apoptosis Flashcards
_______ is the prototypic anti-apoptosis gene
BCL2
how can the BCL2 gene be activated?
Can be activated by translocation from chromosome 18 to the Ig heavy chain locus on chromosome 14
(shift from chromosome 18 to 14)
what is the result of BCL2 over-expression? where is this situation usually seen?
Results in steady accumulation of cells (prevents apoptosis)
– often seen in “low-grade” lymphomas
p53 will upregulate ____, which triggers apoptosis
upregulates BAX gene
its a balancing game between BLC2 and BAX
Tumors cannot grow larger than 1 or 2 mm in diameter unless what occurs?
they are vascularized
how does Angiogenesis facilitates metastases ?
it provides the neoplastic cells access to the vasculature
what are the 2 major steps in invasion/metastasis?
1) invasion of the extracellular matrix
2) vascular dissemination and adhesion/homing of tumor cells
how do tumor cells invade the extracellular matrix?
- Detachment of tumor cells from one another
- Attachment of tumor cells to matrix components
- Degradation of extracellular matrix
- Migration of tumor cells
how can the distribution of tumor metastasis be predicted?
can generally be predicted by the location of the primary tumor and its vascular or lymphatic drainage
lung cancer spreading to adrenal glands, but almost never to skeletal muscle, is an example of what?
organ tropism
what 2 ways can organ tropism occur?
A) Adhesion molecules:
-Organ-specific endothelial adhesion molecules bind tumor cell ligands
B) receptor mediated homing:
-Chemokine receptors on tumor cells home to sites where specific ligands are readily produced
what is Hereditary nonpolyposis colon cancer syndrome? what causes it?
- familial cancers of the colon
- resulting from defective genes involved in DNA mismatch repair
- and evidence of microsatellite instability (MSI).
microsatellite instability (MSI) is seen in ____% of colon cancers
15%
what is Xeroderma pigmentosum? what causes it?
- defective nucleotide excision repair system
- Sunlight (UV light) causes pyrimidine cross-linking in DNA, halting replication
**inability to repair UV damage
what (4) disorders are associated with characterized by hypersensitivity to DNA damage (AKA “fragile DNA” diseases)
Bloom syndrome
ataxia telangiectasia
Fanconi anemia
familial breast cancers (BRCA1 & 2)
what is meant by the concept of “Multistep Carcinogenesis ”?
Cancers typically exhibit multiple genetic alterations including activation of several oncogenes and two or more cancer suppressor genes
what characteristic change as tumors progress through successive “generations”? (how do daughter cells differ)
- they change due to the acquisition of multiple mutations during tumor growth
- results in numerous “subclones” with different characteristics
CML (“Philadelphia chromosome”) is an example of what Karyotypic change?
Balanced Translocations
- translocation between chromosome 22 and 9. As a result, 22 appears shortened
what types of cancers result from karyotypic deletions?
– retinoblastoma (Rb)
- colon cancer
- oral cancer
neuroblastoma and breast cancers are both the result of what Karyotypic change?
Gene amplification
chronic myelogenous leukemia is the result of balanced _________
translocation
- ALB onconogene is translocated from chromosome 9, onto the BCR locus of chromosome 22
During CML, the BCR-ALB hybrid gene will code for what to be produced?
Tyrosine kinase
what are the 3 major classes of carcinogens?
1) chemical
2) radiant energy
3) onconogenic viruses
Percival Pott was the first to discover __________
chemical carcinogens
- linked scrotal cancer (ouch) to the soot from chimneys
what are “indirect carcinogens”
- chemical carcinogens
- they become active only after metabolic conversion
what are procarcinogens ? what are ultimate carcinogens ?
pro-carcinogens: the inactive chemicals that must be metabolized to become carcinogenic
ultimate carcinogens: the compounds created after metabolism of pro-carcinogens
All chemical carcinogens are highly reactive _________, affecting mainly _______
- highly reactive electrophiles
- mainly affect DNA
__________ have little inherent mutagenicity, but drive cells to divide, possibly immortalizing DNA alterations
Promoters
Dentists who held their patients’ films for radiographs often developed what kind of cancer?
squamous cell carcinoma of the index finger
Survivors of the atomic bombs have had a markedly increased incidence of ________ as well as other cancers
leukemia
what is an example of a RNA oncogenic viruses ?
- Human T-Cell Leukemia Virus Type I
- endemic in parts of Japan and Caribbean basin
HPV and EBV (epstein-barr virus) are both ___________ viruses. what types of cancer are they responsible for
DNA onconogenic viruses
- HPV = cervical cancer
- EBV = Burkitt lymphoma
the ______ virus is responsible for Kaposi’s sarcoma
HHV8
hepatocellular carcinoma has been linked to what virus?
Hepatitis B
what is “immune surveillance”
refers to the recognition and destruction of non-self tumor cells when they appear
what are some examples of tumor-specific antigens? what about tumor-associated antigens?
Tumor-specific: Cancer-testis antigens, MAGE-1 (melanoma-associated antigen)
Tumor-associated: prostate-specific antigen (PSA)
_____________ antigens are expressed on normal cells, but will be overexpressed on cancer cells
Tumor-associated antigens
________________ mechanisms are ways by which the body kills tumor cells
Antitumor Effector Mechanisms
what cell types are involved in anti-tumor effector mechanisms?
- cytotoxic T cells (CD8+)
- natural killer cells
- macrophages
- humoral factors
the Selective outgrowth of _____________ variants in tumors helps them evade the bodies immune system
antigen-negative
what is the effect of a tumor cells tendency to lose or reduce the expression of histocompatibility antigens (HLA antigen)?
a lack of HLA antigen means they can avoid attack from cytotoxic T-cells
T cells need _____________ molecules to initiate immune response to foreign antigen
co-stimulatory molecules
- sensitization requires 2nd signal together with foreign antigen
- tumor cells will not produce these molecules, thus avoiding destruction
why would certain benign tumors be more serious than others? (assuming neither will metastasize)
LOCATION of the tumor
- benign tumors that are located in critical areas (such as the pituitary) can be very serious.
adenomas and carcinomas arising from the beta cells of the pancreatic islets may produce _______________
hyperinsulinism
Hormone production is more frequent with what type of tumor?
well-differentiated, benign tumors
what is “Cachexia” characterized by?
Characterized by progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia and anemia
__________ is usually a terminal event associated with advanced cancer
cachexia
why is Paraneoplastic syndrome important in the treatment of cancer?
- May represent an early manifestation of occult disease
- May pose significant clinical problems for affected patients
- May mimic metastatic disease and thereby confound treatment
what are some examples of paraneoplastic syndromes?
A) hypercalcemia
B) Cushing’s syndrome
C) nonbacterial thrombotic endocarditis
D) paraneoplastic pemphigus
what is a disease prognosis?
defining the grade and stage of a malignancy, we attempt to predict the course of the disease, both with or without treatment
grading attempts to assess the _______________ of a malignancy
aggressiveness
how are malignancies graded?
- Grades can range from I to IV, depending on the particular type of cancer
- Grade I representing the most differentiated and Grade IV, the least.
_________ is a method of estimating cancer size or EXTENT
staging
how is cancer staging assessed?
the size of the primary lesion
lymph node involvement
and metastatic spread (TNM system)
what biochemical assays are used to diagnose cancer?
prostate-specific antigen (PSA)
carcinoembryonic antigen (CEA)
α-fetoprotein
what molecular diagnosis are used to diagnose cancer?
FISH
PCR
Paraneoplastic syndromes are seen in what % of cancer patients?
10-15%
