upregulates BAX, which disrupts Bcl2 leading to cytochrome c leaks from the mitochondria activating apoptosis
Knudson two-hit hypothesis
both copies of the p53 gene must be knocked out for tumor formation, Both copies of Rb gene must be knocked out for tumor formation
Loss of p53 is seen in what percentage of cancers?
>50% of cancers.
Germline mutation results in
Li-Fraumeni syndrome (2nd hit is somatic),
Li-Fraumeni syndrome is characterized by?
the propensity to develop multiple types of carcinomas and sarcomas,
regulates progression from G0 to S phase.
How does Rb regulate the progression to S phase?
holds the E2F transcription factor, which is necessary for transition to the S phase
E2F is released when?
RB is phosphorylated by the cyclinD/cyclin-dependent kinase 4 (CDK4) complex
Rb mutation results in
constitutively free E2F, allowing progression through the cell cycle and uncontrolled growth of cells.
(both hits are somatic) and it is characterized by unilateral retinoblastoma
Germline mutation results in
familial retinoblastoma (2nd hit is somatic) and is characterized by bilateral retinoblastoma and osteosarcoma.
What is the function of regulators of apoptosis?
Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g Bcl2)
normally stabilizes the mitochondrial membrane, blocking release of cytochrome c
Disruption of Bcl2 allows what to happen?
Cytochrome c to leave the mitochondria and activate apoptosis
Bcl2 in follicular lymphoma?
it is overexpressed in follicular lymphoma,
Why is Bcl2 overexpressed in follicular lymphoma?
t(14;18) moves Bcl2 (chromosome 18) to the Ig heavy chain locus (chromosome 14), resulting in increased Bcl2.
How is apoptosis inhibited in follicular lymphoma?
Mitochondrial membrane is further stabilized by overexpressed Bcl2, prohibiting apoptosis.
In follicular lymphoma, how does the inhibition of apoptosis lead to lymphoma?
B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate, leading to lymphoma.
What is necessary for cell immortality?
Normally telomeres do what?
shorten with serial cell divisions, eventually resulting in cellular senescence
What is the relationship between cancers and telomerase?
cancers often have up regulated telomerase, which preserves telomeres
Angiogenesis and tumors
(production of new blood vessels) is necessary for tumor survival and growth.
FGF and VEGF
(angiogenic factors) are commonly produced by tumor cells.
Tumor survival and the immune system?
Avoiding immune surveillance is necessary for tumor survival
Immune surveillance and tumor survival?
Mutations often result in production of abnormal proteins, which are expressed on MHC class 1, CD8+ T cells detect and destroy such mutated cells, Tumor cells can evade immune surveillance by downregulating expression of MHC class 1.
How do tumor cells evade immune surveillance?
by downregulating MHC class 1
Immunodeficiency and cancer
(both primary and secondary) increases risk for cancer
Accumulation of mutations eventually result in what?
tumor invasion and spread
Epithelial tumor cells are normally attached to one another by what?
cellular adhesion molecules (e.g., E-cadherin).
Downregulalion of E-cadherin leads to what?
dissociation of attached cells
How do the tumor cells spread locally?
Cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase. Cells attach to fibronectin in the extracellular matrix and spread locally
Metastasis of tumor cells.
Entrance into vascular or lymphatic spaces allows for metastasis (distant spread)
What are the routes of metastasis?
Lymphatic, hematogenous, seeding of body cavities
Lymphatic spread is characteristic of what?
Where does the initial lymphatic spread occur?
In the regional draining lymph nodes
Hematogenous spread is characteristic of what?
sarcomas and some carcinomas
What are some examples of hematogenous spread?
renal cell carcinoma, hepatocellular carcinoma, follicular carcimoma of the thyroid, choriocarcinoma
Seeding of body cavities is characteristic of?
ovarian carcinoma, often involves the peritoneum 'omental caking'
What is omental caking?
where the peritoneum is often involved in ovarian carcinoma
Describe benign tumors.
tend to be slow growing, well circumscribed, distinct, and mobile
Malignant tumors are usually
rapid growing, poorly circumscribed, infiltrative, and fixed to surrounding tissues and local structures.
What is generally required before a tumor can be classified as benign or malignant with certainty?
Biopsy or excision
Why is biopsy necessary?
Some benign tumors can grow in a malignant-like fashion, and some malignant tumors can grow in a benign-like fashion.
Benign tumors are usually
What are some characteristics of benign tumors?
1. Organized growth 2. Uniform nuclei 3. Low nuclear to cytoplasmic ratio 4. Minimal mitotic activity 5. Lack of invasion (of basement membrane or local tissue) 6. No metastatic potential
Malignant tumors are classically
poorly differentiated (anaplastic)
Characteristics of malignant tumors include
1. Disorganized growth (loss of polarity) 2. Nuclear pleomorphism and hyperchromasia 3. High nuclear to cytoplasmic ratio 4. High mitotic activity with atypical mitosis 5. Invasion (through basement membrane or into local tissue)
What is the hallmark of malignancy?
Metastatic potential - benign tumors never metastasize
What is the target cell type for the immunohistochemical stain of Keratin?
What is the target cell type for the immunohistochemical stain of Vimentin
What is the target cell type for the immunohistochemical stain of desmin
What is the target cell type for the immunohistochemical stain of GEAP
What is the target cell type for the immunohistochemical stain of Neurofilament
What is the target cell type for the immunohistochemical stain of PSA
Prostatic epil helium
What is the target cell type for the immunohistochemical stain of ER
What is the target cell type for the immunohistochemical stain of Thyroglobulin
thyroid follicular cells
What is the target cell type for the immunohistochemical stain of chromogranin?
neuroendocrine cells (small cell carcinoma of lung and carcinoid tumors)
What is the target cell type for the immunohistochemical stain of S-100?
What is used to characterize tumors that are difficult to classify on histology?
What are serum tumor markers?
Proteins released by tumor into serum (e.g PSA)
Serum tumor markers are useful for what?
screening, monitoring response to treatment, and monitoring recurrence
Elevated levels of serum tissue markers require what?
it requires tissue biopsy for diagnosis of carcinoma (e.g., biopsy of prostate with elevated PSA),
What is involved in the grading of cancer?
Microscopic assessment of differentiation (how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features
What is low grade?
Well differentiatedresembles normal parent tissue
What is high grade?
poorly differentiateddoes not resemble parent tissue
Cancer grading is important for what?
determining prognosis; well-differentiated cancers have better prognosis than poorly-differentiated cancers.
What is staging of cancer?
its an assessment of size and spread of a cancer,
How does the staging of cancer compare to the grading of cancer?
Key prognostic factor; more important than grading
When is the staging of cancer determined?
after final surgical resection of the tumor
What is the TNM staging system?
Ttumor (size and/or depth of invasion), Nspread to regional lymph nodes; second most important prognostic factor, Mmetastasis; single most important prognostic factor
In the TNM staging system what is the most important prognostic factor?