Neoplasia III Flashcards
BCL2. What is it and how is it activated?
The prototypic anti-apoptosis gene
Can be activated by translocation from chromosome 18 to the Ig heavy chain locus on chromosome 14
What happens when BCL2 is over-expressed?
Protects cells from apoptosis, allowing them to survive for prolonged periods
Results in steady accumulation of cells - often seen in “low-grade” lymphomas
Tumors grow slowly not because cells are proliferating, they just aren’t dying
Sustained Angiogenesis
Even with multiple genetic abnormalities, tumors cannot exceed 1-2 mm in diameter unless they are vascularized
Angiogenesis facilitates metastases - provides access to the vasculature
T/F - all cells are capable of metastasizing
False - Only certain subclones may be capable of metastasizing
What are the two phases of Invasion and Metastasis?
1) Invasion of ECM
2) Vascular dissemination and adhesion/homing of tumor cells
Steps of Invasion of ECM
1) Tumor cells detach from one another
2) They attach to ECM components (collagens, glycoproteins, and proteoglycans)
3) They degrade matrix components
4) Migration of tumor cells
Once in circulation, tumor cells are vulnerable to what?
Destruction by the host immune cells
How can the distribution of tumor metastases be predicted?
Based of the location of the primary tumor and its vascular and/or lymphatic drainage
Organ tropism
Sometimes seen in metastases
a. Organ-specific endothelial adhesion molecules bind tumor cell ligands
b. Chemokine receptors on tumor cells home to tumor cells home to sites where specific ligands are readily produces
What is critical to integrity of genome and control of cellular growth?
DNA repair
Patients with inherited defects in DNA repair have what?
Increased risk for cancer
If errors in DNA replication occur naturally, why isn’t cancer more common?
DNA repair genes - they’re pretty reliable
Hereditary nonpolyposis colon cancer sydrome
Familial cancers of the colon resulting from defective genes involved in DNA mismatch repair and evidence of microsatellite instability
Xeroderma pigmentosum
Defective nucleotide excision repair system
Sunlight (UV light) causes pyrimidine cross-linking in DNA, halting replication
Lacking ability to excise and repair their altered residues leads XP patients at risk for cancer
Bloom Syndrome, Ataxia telangiectasia, Fanconi anemia
Disorders characterized by hypersensitivity to DNA damage
Patients have increased cancer risk and other health problems
BRCA1 and BRCA2
Genes involved with repair of dsDNA breaks, may also have tumor suppressor roles
Patients are at risk for other forms of cancer besides breast cancer
Multistep carcinogenesis
No single mutation results in cancer
Cancers typically exhibit multiple genetic alterations including activation of several oncogenes and two or more cancer suppressor genes
What is the epidemiological evidence for multiple step carcinogenesis?
Cancer is more likely to occur in older people
Tumor Progression and Heterogeneity
Tumors begin as a monoclonal proliferation of one transformed cell. As daughter cells divide, they tend to develop more and more mutations
By the time a tumor mass is formed, the cells may be quite heterogeneous in many lesions
The subclones may be able to survive certain therapies, invade certain host tissue, or metastasize with greater efficiency
What are the different Karyotypic Changes in Tumors?
Balanced Translocations
Deletions
Gene amplifications
Balanced translocations
Extremely common, especially in hematopoeitic neoplasms
example: CML (philladelphia chromosomes) - translocation between chromosomes 9 and 22, causing 22 to become shorter
Deletions
Second most prevalent form of karyotypic abnormalitites in tumores
example: 3p, 9p, and 17p are common areas of loss in oral cancers
Gene amplifications
Seen in neuroblastoma and some breast cancers
What are the three major classes of carcinogenic agents?
Chemicals
Radiant energy
Oncogenic viruses
Sir Percival Pott
200 yrs ago described scrotal skin cancer in chimney sweeps and attributed it to chronic exposure to soot
Procarcinogens
Most carcinogens are indirect and require some metabolic conversion
Procarcinogens are before the conversion
What are the end products of procarcinogens?
Ultimate carcinogens
All carcinogens are what? How do they cause damage?
Highly reactive electrophiles, interacting with the electron-rich DNA molecule and inducing genetic damage
Some carcinogens can be augmented by what? How does this work?
Promoters (agents that have little inherent transforming ability)
The carcinogen is thought to serve as the initiator of a mutagenic event, while the promotor drives replication of the damaged cell
What are some examples of radiation carcinogenesis?
UV - skin cancers
X-rays - early dentists got simp. sqau. cell carcinoma on their fingers from holding films
Radionuclides - miners of radioactive elements and lung cancer
Gamma radiation from nuclear fission - atomic bomb survivors had cancer with 8-12 yr latency
What is the latency of radiation and cancer
Usually long after exposure (7-12 years)
What are the different types of viral oncogene viruses?
RNA oncogene viruses
DNA oncogene viruses
DNA oncogene viruses
Transforming DNA viruses from stable associations with the host genome
What are some different DNA oncogene viruses?
HPV - leads to benign squamous papillomas or uterine cancers
EBV - implicates several human malignancies
HBV - linked to development of hepatocellular carcinoma
Tumor immunity/surveillance
The recognition and destruction of non-self tumor cells when they appear
Not a perfect system, otherwise there’d be no cancer
What are the different tumor surveillance mechanisms?
Tumor antigens
Antitumor effector mechanisms
Immunosurveillance
Tumor-specific antigens
Only associated with tumor cells
Tumor-associated antigens
These are antigens that may be found on normal cells, but may be over-expressed or represent a specialized function of the cells (differentiation-specific antigens)
Antitumor Effector mechanisms
These are ways in which the body kills tumors
- Cytotoxic T-cells
- Natural killer cells
- Macrophages
- Humoral mechanisms
Cytotoxic T lymphocytes (CD8+)
Play a role against virus-induced neoplasms
Natural killer cells
Lymphocytes that kill tumor cells without prior sensitization
May be the first line of defense against tumors
Macrophages
May collaborate with T cells and NK cells to destroy tumor cells
May act by mechanisms used to destroy microbes or by producing TNF-a
Humoral mechanisms
Either activation of compliment or induction of antibody-dependent cytotoxicity by NK cells
What is the strongest argument for immunosurveilance?
Increased frequency of cancer is observed in immunocompromised
How can tumors evade the immune system?
Selective outgrowth of antigen-negative variants
Loss or reduced expression of histocompatability antigens
Lack of T-cell co-stimulation
Immunosuppression
Selective outgrowth of antigen-negative variants
Subclones that are most immunogenic to the host are destroyed, leaving the subclones that are relatively antigen-negative
Loss of reduced expression of histocompatability antigens
Tumor cells not express normal levels of HLA class I, thereby escaping attach by cytotoxic T cells
Location effect of tumors on host
Eventhough malignancies are of great concern, benign tumors that are located in critical areas can be very serious
Tumor effects on hormone production
Adenomas and carcinomas arising from the beta cells of the pancreatic islets may produce hyperinsulism, which may be fatal
Hormone production is more frequent with well-differentiated, benign tumors
Ulceration of host with tumors
When a tumor expands to the point of breaking through an epithelial surface, problems with bleeding and secondary infection can arise
Cachexia
Seen in cancer patients
Characterized by progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia, and anemia
Usually a terminal event associated with advanced cancer
Process not fully understood
Parenoplastic syndromes
Occur in 10-15% of cancer patients
May represent and early manifestation of occult disease
May pose significant clinical problems for affected patients
May mimic metatastic disease and thereby confound treatment
Grading of cancer
Refers to an estimate of the aggressiveness of a cancer
Based on the microscopic appearance
Staging of cancer
Describes the cancer extent - size of primary lesion, lymph node involvement, metatastic spread
Estimated by clinical exam and imaging
What are the types of labratory diagnosis of cancer
Biopsy Electron microscopy Frozen section biopsy Fine-needle aspiration biopsy Cytologic (Pap) smear Flow cytometry Biochemical assays Molecular diagnoses
Incisional biopsy
Portion of the lesion is taken for microscopic examination
Excisional biopsy
Entire lesion is removed for microscopic examination
