Neoplasia II Flashcards
Metastasis definition
Development of secondary deposits of a tumor in a distant site
Considered the hallmark of malignancy (but not always seen)
T/F - All cancers have the same rate of metastasis
False - some types of cancer metastasize
How often do tumors metastasize?
30% of newly diagnosed patients with solid tumors will already have obvious metastases
Another 20% will have occult metastases
What kinds of tumors are more likely to metastases
In general, the larger and more anaplastic (less differentiated) a tumor is, the more likely it is to metastasize
What are the ways Metastasis spread?
Seeding within body cavities
Lymphatic spread
Hematogenous spread
Lymphatic spread of metastasis
Usually seen with carcinomas
Lymph nodes are involved - leads to lymph node metastases
Hematogenous spread
Usually seen with sarcomas
Liver and lungs are most often affected
Cancer Epidemeology
Often provides clues as to the etiology (cause) of or contributing factors to cancer development
Geography and Environment effect on cancer
Sometimes clues as to cancer etiology can be obtained by looking at the cancer incidence of specific countries, populations, or geographic regions and identifying particular habits, dietary features, etc that might contribute to an increased incidence of a particular type of cancer
How does age effect cancer rate
Cancer frequency often increases with age
Most cancer mortality occurs between 55-75 years of age
Yet, 10% of deaths among children
Heredity of Cancer
Cancer occurs in 1 of 5 people
There are predisposing factors for some cancers, but well-defined genetic influences are only identified in a few
What are the 3 broad categories of genetic predisposition to cancer
1) Inherited cancer syndromes
2) Familial cancers
3) Defective DNA repair
Inherited Cancer
Usually due to a single gene mutation and generally show autosomal dominant transmission examples: -Retinoblastoma -Familial adematous polyposis -Multiple endocrine neoplasia
Familial Cancers
Early age at onset
Tumors arising in two or more close relatives of the index case
Colon, breast, ovary and brain malignancies have been reported to occur in familial patterns
What are some Acquired Preneoplastic Disorders?
Increased liklihood of cancer in:
- persistent regenerative cell replication
- villous adenomas of the colon
- leukoplakia of oral or genital mucosa
What lies at the heart of carcinogenesis?
Nonlethal genetic damage
The fact that most cancers are clonal proliferations suggests what?
That tumors arise from one genetically altered cell
What are the 3 classes of normal regulatory genes that are often effected in carcinogenesis?
Protooncogenes - growth promoting
Cancer suppressor genes - growth inhibiting
Apoptosis genes
DNA repair genes
Indirectly contribute to cancer development since acquire mutations can’t be repaired
-if these genes are disabled, the frequency of mutations increases, and the rate of neoplastic transformation increases
T/F - Carcinogenesis is a multi-step process
True - at both the phenotypic and genetic levels
What are the products of oncogenes?
Oncoproteins
How are protooncogenes transformed to oncogenes?
1) Structural mutation of the gene, resulting in an abnormal product
2) Altered regulation of gene expression, resulting in increased production of a normal growth-promoting pattern
What are some examples of proteins that when are effected can lead to uncontrolled promotion of cell growth?
Growth Factor Growth Factor receptors Signal-transducing proteins Nuclear transcription Cyclins and cyclin-dependent kinases
Growth Factors oncoproteins
All normal cells require growth factor stimulation to undergo proliferation
examples:
-platelet derived growth factor (PDGF)
-TGFa
Growth Factor Receptor oncoproteins
Mutations and over expression of growth factor receptors have been documented
Mutant receptor proteins deliver continuous mitogenic signals
Overexpression makes cancer cells hyperresponsive to even normal GF levels
Signal-Transducing oncoProteins
RAS - approximately 20% of all human tumors contain mutated RAS oncogene
Normally inactivated quickly, mutant RAS remains in its active form, stimulating constant cell proliferation
Nuclear Transcription Factor oncoproteins
MYC gene is most commonly effected
MYC gene dysregulation leads to overexpression, leading in continuous activation of cyclin-dependent kinases (CDKs) driving the cell to divide
MYC also represses CDK inhibitors
Cyclins and Cyclin-dependent Kinase oncoproteins
Orderly progression of cell cycle is orchestrated by CDKs following activation by binding to cyclins
Activity of CDKs is regulated by two families of CDK inhibitors (CDKIs)
Dysregulation favors cell proliferation
Tumor Supression Genes
Products inhibit cell proliferation
RB (retinoblastoma) gene was first to be discovered - products regulates transcription
Products are generally less understood than those of oncogenes
Regulate cell cycle, cell adhesion, signal transduction
Knudson’s “two-hit” hypothesis
Two mutations (“hits”) in the genome of a cell required to induce retinoblastoma
Genetics of retinoblastoma
In familial cases, child inherits one defective copy of the RB gene, and the other is normal
When normal RB gene undergoes somatic mutation, a tumor develops
TP53 overview
Important example of tumor supressor gene
Single most common target for genetic alteration in human tumors
Homozygous loss of TP53 is found in virtually all types of cancer
Mutations that inactivate both copies of the TP53 gene usually in acquired change in somatic cells
Where/how does TP53 normally act?
Normally acts in the nucleus to inhibit cell cycle progression
When DNA is damaged, TP53 accumulates, inhibiting cell proliferation and allowing the DNA to repair
If repair mechanisms fail, TP53 activates apoptosis genes
Homozygous loss/mutation of TP53
DNA damage goes unrepaired
Mutations become fixed in dividing cells
Leads to uncontrolled cell division: cancer
Li-Fraumeni syndrome
Inherited defect of one TP53 allele
25x increased risk for malignancy before age 50
