Tumors that are monoclonal develop into widely varying cell types (i.e. teeth and hair). Pleomorphic.
Tumors that contain tissue from more than one germ cell layer. These often come from totipotent cells
Benign tumor differentiation
Neoplastic cells are well-differentiated and closely resemble the surrounding parenchyma
Why are malignant tumors more difficult to diagnose pathologically than benign tumors?
Malignant neoplastic cells vary greatly in differentiation and anaplasia.
Hallmarks of malignancy
Anaplastic neoplasms, hyperchromatic nucleus, mitoses (abnormal cell divisions), loss of polarity, ischemic necrosis and giant cells.
*What do you see?
Benign, well differentiated tumor in the uterus
*What do you see?
Anaplastic tumor. Note pleomorphism, hyperchromatic nuclei and giant tumor cells
*What do you see?
Anaplastic tumor. Note abnormal tripolar spindle in center cell.
What often occurs in metaplastic epithelial tissue?
Dysplasia = loss of uniformity of individual cell and architecture
When is a carcinoma considered to be invasive?
Once it breaches the basement membrane. Before that, it is an in situ carcinoma
What clinical aspect of neoplasia makes detection difficult?
By the time you find a solid tumor most of its cells are no longer in the replicative pool.
What determines the rate at which a tumor grows?
Doubling time, growth fraction (number of cells in replicative pool) and rate of cell death
Where do most tumor cells go when they leave the replicative pool?
What ultimately determines how fast a tumor grows.
Cell production and cell loss ratio
Why does radiation or surgery normally precede chemotherapy?
Chemotherapy drugs are effective against drugs in the cell cycle. Since many cells in the tumor are in G0, radiation and surgery debulk the tumor to try and get the cells back into replication phase.
What physiological factors can increase or decrease tumor growth over time?
Hormonal stimulation or blood supply
Why are malignant stem cells generally non responsive to current therapies?
Stem cells have a low level of cell division and express drug resistant factors.
*What do you see?
Benign breast tumor. Note connective tissue border that prevents to tumor from spreading into surrounding tissues.
*What do you see?
Malignant breast tumor. Note invasion of breast stroma, absence of capsule, fat in nests and cords of tumor cells
What are the two most reliable features that differentiate a malignant tumor from a benign tumor?
1. Metastasis 2. Invasiveness
What malignant tumors do not usually metastasize?
Gliomas (glial cells in the CNS)
What three ways does cancer normally spread?
Seeding, lymphatic spread and hematogenous spread.
Where does seeding most often occur?
What is the most common mode of cancer spread?
What lymphatics are most likely to be affected when cancer spreads?
Lymph node closest to the primary site of neoplasia
A patient experiences swollen lymph nodes and a lump on her breast. What do you suspect regarding tumor metastasis?
Possible metastasis due to migration to lymph node. Possible cancer arrest within the lymph node.
What organs are most often affected by cancers that migrate hematogenously?
Liver and lungs. Cancer gets into veins easier because they are thinner and most veins go through the liver and lungs.
*What do you see?
Metastatic nodule from pancreas in the liver
Genetic factors that may predispose someone to cancer
Autosomal dominant: stay in a particular place w/particular phenotype, Defective DNA-repair, Familial cancers: combination of multiple low-penetrance alleles
Why would physicians prescribe COX-2 inhibitor to a colon cancer patient?
Chronic inflammation and its mediators are linked to development of cancer.
What are the four classes of regulatory genes in neoplasia?
Proto-oncogenes, tumor suppressor genes, apoptosis genes, and DNA-repair genes.
7 Cellular Physiological Changes That Determine Malignancy
Proliferation w/o external stimuli, Nonresponsive to strong inhibitory stimuli, Inactivation of apoptotic genes (p53), Limitless replicative potential, Angiogenesis, Ability to invade and metastasize, and DNA repair defects
How do growth factors contribute to development of neoplasms?
They activate receptors that activate, most often, a portion of the signal pathway that fell prey to oncogenes. That portion greatly amplifies the signal transduction and proliferation of the cell.
What receptors are particularly susceptible to oncogene mutations?
Tyrosine kinase receptors. They phosphorylate each other and can remain in an activating state without any stimulus.
Why might growth factor receptors be good targets for targeted cancer therapy?
Growth factor related cancers usually have a receptor mutation. Targeting receptors is fairly easy compared to other methods.
Most common abnormality of proto-oncogenes in human tumors?
Point mutations in RAS or its GEF, which activates the MAP kinase pathway which signals for cell proliferation.
What gene influences receptor kinase mutations that are not growth factor related?
Translocation of ABL gene from chromosome 9 to chromosome 22. JAK2 activation and STAT induces proliferation.
This transcription factor is thought to play a role in cancer by activating more origins than needed during DNA replication.
What cyclins are most commonly mutated in patients with tumors?
Why would a mutation in p21, p27, or p57 put someone at a high risk for cancer?
They inhibit CDKs widely and mutations would activate CDKs and the cell cycle widely.
What phase of the cell cycle prevents replication of cells with DNA defects?
G1/S checkpoint. Induces apoptotic pathways if the DNA is not repaired.
Defects at which part of the cell cycle give chromosomal abnormalities?
G2/M checkpoint. If DNA does not replicate properly and chromatids cannot separate properly, cells are arrested in G2.
What sensors and transducers are used at the cell cycle checkpoints?
Sensors: RAD family and ATM. Transducers: CHK kinases
What effector molecules regulate at the G1/S checkpoint?
p53 induces cell cycle inhibitor p21
What effector molecules regulate at the G2/M checkpoint?
p53 and other mechanisms
When does someone become cancerous because of the RB gene?
When both RB genes are mutated and it loses its tumor suppressor function.
How does hypophosphorylated RB block the G1/S phase transition?
It sequesters E2F and recruits chromatin-remodeling proteins to bind to promoter regions and render promoters insensitive to transcription factors.
Why is the transcription factor E2F important in the cell cycle?
It controls expression of cyclin E. Initiation of DNA replication requires cyclin E-CDK2 complexes.
What changes RB to activate the cell cycle?
Cyclin D-CDK4/6 complexes phosphorylate RB, inactivating it and causing it to release E2F which then induces cyclin E production.
How can a mutation in on of the four key regulators of the cell cycle mimic RB mutations?
Cyclin D overexpression and CDK4 activation phosphorylate RB and keep it activated. p16/INK4a mutation fails to inactivate cyclin D/CDK4.
How does HPV cause cervical cancers?
It binds strongly to the same RB pocket E2F binds, leaving E2F free to activate replication wherever it pleases. It also binds p53 and inactivates it.
RB regulation pathway
People have 25x greater chance of developing a tumor by age 50 because of mutation of on p53 gene.
How can a mutation negatively affect a p53 pathway when p53 is not mutated?
MDM2 overexpression causes over-degradation of p53 transcription factor
What does p53 go on to do when released from MDM2?
Causes cell cycle arrest and apoptosis/senescence if DNA is not repaired
DNA damage in a cell with normal p53 function
Activated p53 binds DNA_p21 inhibits CDK and DNA repair initiates_G1 arrest_Successful repair = normal cells, Failed repair = BAX gene-induced apoptosis
DNA damage in a cell with mutated p53
DNA damage and p53 interaction with miRNAs
Activated p53 binds DNA_mir34 transcribed and processed_inhibition of growth-promoting genes (MYC,CDK4) and anti-apoptotic genes (BCL-2)_Quiescence/senescence or apoptosis
How is the DNA damage repair pathway initiated?
ATM and ATR sense damage and phosphorylate p53
What is p53's role in G1 cell cycle arrest?
Activates transcription of p21 which inhibits cyclin-CDK complexes and phosphorylation of RB.
What happens if DNA is successfully repaired?
p53 upregulates transcription of MDM2, which inhibits p53
Why might DNA repair be induced first by p53 over cell apoptosis?
p53 has a higher affinity for DNA repair promoters and it activates those first.
How does chemotherapy and irradiation target neoplastic cells with functional p53 genes?
They induce DNA damage and apoptosis by functional p53 activation.
What is the likely cause of cancer in the liver after years of Hep B infection?
Aside from regenerative hyperplasia, HBV's regulatory element, HBx inactivates p53.
What can increase a tumor's chance of metastasis?
Heterogeneity, maybe there's a cell in there that can make the journey. Increases laminin expression for binding to distant basement membranes.
How do familial tumors usually act?
Usually come from a defected tumor suppressor gene.
How would a p16 familial mutation affect a cell?
It would no longer be able to block RB phosphorylation. CDKs would be activated and cells would proliferate.
What results from an NF1 mutation?
RAS-GTP activity signals constant transduction. Results in neurofibromatosis type I
Why can chemicals be precursor to cancer?
Many are electrophiles and bind to negatively charged DNA. They mutate the DNA and cause cancer.
What might a patient in the sun experience as a result of decrease nucleotide excision repair?
Xeroderma pigmentosum. UV damage remains permanent.
How does mutation of MYC gene affect cells?
Transcription is activated and microsatellites become unstable. This results in nonfunctional DNA repair enzymes.
What is BCL-2's role in cancer?
Anti-apoptosis, continuously stimulated when the gene translocates to a near Ig heavy chain gene.
How could you diagnose monoclonal cells?
Southern blot. It can be used to differentiate T and B cell rearrangements)
This substance is known to cause liver angiosarcomas.
This substance is known to cause the gastric cancer marginal zone lymphoma.
What do BRCA1 and BRCA2 genes code for?
DNA repair enzymes
What chemical is known to cause skin cancers?
What chemicals can cause lung cancers?
Asbestos and beryllium
What chemicals can cause upper reparatory tract cancers?
What chemicals can cause urinary tract cancers?
What gives neoplasms the quality of highly invasive?
Cathespin D. It can degrade fibronectin and laminin, clearing a path for the advancing tumor. MMP9 degrades type IV collagen.
What marker would you look for in hepatocellular carcinomas?
What marker would you look for in myelomas?
Ig levels with electrophoresis
What marker would you look for in GI and pancreatic cancers?
What cancers produce symptoms similar to Cushing's Syndrome?
Small cell lung carcinomas. They secrete corticotropin.
What cancers produce symptoms of hypercalcemia?
Pulmonary squamous cell carcinomas due to parathyroid-like hormone secretion.
What cancers produce increased levels of erythropoeitin?
What cancers produce increased levels of insulin and gastrin?
Benign, glandular epithelial surface tumors.
Benign mass of foreign tissue compared to the tissue surrounding it
Why is a functional APC crucial in regulating the WNT signaling pathway?
Red benign skin tumor
Where do fibroadenomas usually form?
Light brown benign skin tumor
Where do EGF mutations most often occur?
Squamous cell carcinoma of the lung
How can cancer be induced in hypoxic conditions?
HIF1alpha needs oxygen to bind and inactivate VHL. In hypoxic environments, VHL escapes HIF1alpha and turns of VEGF and PDGF to stimulate proliferation
What type of cancer is linked to non-functional APC?
Familial Adenomatous Polyposis
What colon cancers stem from defects in mismatch repair?
HNPCC syndrome. Patients inherit one mismatch repair enzyme that doesn't work. A second hit results in microsatellite instability and possible cancer.
What causes Burkitt lymphoma?
Translocation of the MYC gene next to an Ig heavy chain so that it is overexpressed and you get lots of cyclin production which activates cell proliferation. Common with EBV infection.
What causes chronic myelogenous leukemia?
BCR-ABL fusion, resulting in uncontrolled tyrosine kinase activity
How does TGF-beta inhibit proliferation?
Activates transcription of CDKIs and decreases proliferation.
What cancers stem from BCL1 and BCL2?
What regulates cachexia in malignant cancers?
How can you detect gene amplification?
Observation of double minutes and homogenous staining regions.
What happens as a result of PTEN mutation?
Upregulation of PI3K/AKT signaling which enhances cell survival and promotes growth.
How do tumors detach from the ECM?
Downregulation of E-cadhedrins
What happens molecularly in an ATM mutation?
The protein is no longer able to sense double-stranded breaks and does not arrest the cell cycle or cause arrest.
Tumor cells need to shunt lipids and nucleotides to new cell production. Consequently, they rely on glycolysis for energy.
Indirect acting agents
Chemicals requiring metabolic conversion by P-450 before becoming carcinogenic.
What virus inactivates p16 and what are its effects?
HTLV-1. Its encoded Tax protein inactivates p16 and cell replication increases. It also activates transcription factor NF-kappaB
How do B-cells become immortal?
EBV. Its protein LMP-1 activates NF-kappaB and JAK/STAT pathways.
What is tumor grading?
Degree of tumor differentiation and architecture.
What is staging?
Tumor size and spread. TNM classification is T (tumor size) N (regional lymph node involvement) and M (metastases)