Neoplasia Flashcards
Example of Cells synthesizing their own Growth Factor
Glioblastomas secrete PDGF (platelet derived GF) and express PDGF receptor.
Sarcomas cn make Transforming GF-alpha and its receptor. Autocrine loops.
Ex. Of overexpressed Growth factor receptors
ERBB1, the EGF receptor is over-expressed in 80% of SCC of the lung, and 80-100% of epithelial tumors of the head and neck.
ERBB2/HER2 a related receptor is amplified in 20% of breast cancers.
Siignalling enzyme mutations downstream from growth factor receptors, examples.
RAS and ABL
Example of Transcription factor mutations.
MYC, JUN, FOS are oncogenes that produce oncoproteins which function as transcription factors that regulate expression of growth promoting genes such as cyclins and CDKs.
Ex of precursor lesions
Squamous metaplasia of bronchial mucosa - smokers.
Endometrial hyperplasia- unopposed estrogen stimulation.
Leukoplakia of oral cavity, genitalia- can progress to SCC.
Villous adenoma of the colon- can progress to colorectal carcinoma.
Parenchyma of tumors
Made up of transformed or neoplastic cells. Determines its biologic behavior, derives name from this component.
Stroma
Host derived, supporting tissue of the tumor. Connective tissue, blood vessels, host derived inflammatory cells. Crucial to growth of the neoplasm.
Suffix used for benign tumors
-oma
Adenoma
Tumor arising from glandular epithelia.
Papilloma
Benign neoplasms of epithelia with finger-like projections.
Polyp
Mass that projects above a mucosal surface. Macroscopically visible.
Sarcoma
Malignant tumor of the solid mesenchymal tissues or its derivatives. Designated based on cell type composition, i.e. liposarcoma, chondrosarcoma.
Leukemia/Lymphoma
Cancer arising from the mesenchymal cells of the blood.
Carcinoma
Cancer arising from epithelial cells. They are usually poorly differentiated.
Adenocarcinoma
Carcinomas that grow in a glandular pattern.
Squamous cell carcinoma
Carcinoma that produces squamous cells.
Differentiation (of neoplasms)
Extent to which they resemble their cells of origin, morphologically and functionally. In general benign tumors are well differentiation, malignant tumors are not. However in well differentiated malignant tumors, morphological features may be difficult to spot.
Anaplasia
Lack of cell differentiation.
Pleomorphism
Variation in size and shape of cells and their components. Characteristic of anaplasia.
Nuclear abnormalities
Extreme hyperchromatism, size and shape abnormalities, unusually prominent nucleoli.
Characteristic of anaplasia
Atypical mitoses
May be numerous. Examples like multipolar spindles, asymetry of poles, abnormal chromatid separation or lagging. Characteristic of anaplasia.
Loss of polarity
Cells lack recognizable patterns of orientation to one another. Characteristic fo anaplasia.
well-differentiated tumors
Can often continue normal function, endocrine tumors can continue to produce normal hormones, but possibly at an abnormal rate.
Local invasion
In cancer: Progressive infiltration, invasion, and destruction of surrounding tissues.
In benign tumors: cohesive expansile masses that remain localized.
See: leiomoyoma of myometrium vs. leiomyosarcoma.
Capsule
Rim of compressed fibrous tissue around benign tumor. Deposited by stromal fibroblasts. Makes tumor moveable and easily excised.
Invasiveness
Cancers lack well defined capsules and edges. They are non-moveable masses and invade the surrounding tissue.
Metastasis
Spread of tumor to sites that are physically discontinuous. Marks a tumor as malignant. 30% of patients with a new tumor have evident metastases. 20% have occult metastases.
Seeding within body cavities
Neoplasms invade a natural body cavity, such as the peritoneum. Characteristic of ovarian cancers.
Lymphatic spread
Metastases through the lymph system. Will usually accumulate in lymph nodes. Favored by carcinomas.
Hematogenous spread
Metastasis through blood vessels. Liver and lungs favored as secondary sites. Favored by Sarcomas. Tumor cells will accumulate in the 1st capillary bed they encounter.
Pattern of lymph spread of breast cancers
Axillary or internal mammary nodes (depending on location) then supraclavicular or infraclavicular nodes. 60% of breast cancers are located in the lateral upper quadrant.
Paraneoplastic syndromes
Symptom complexes in cancer patients that can’t be explained by local invasion, metastasis, or by elaboration of hormones of the tumors native tissue. Can be Endocrine, Hematologic, Osteoarticular, Cutaneous, or Neurologic.
Hypercalcemia (Paraneoplastic)
Can be due to tumor production of parathyroid hormone related protein (PTHrP). Breast, non small cell lung, squamous cell of the head and neck cancers can secrete this.
Cushing Syndrome
Usually related to ectopic production of ACTH or ACTH-like polypeptides by cancer cells.
Hypercoaguability
Can lead to DVT and nonbacterial thrombic endocarditis.
Tumor Grading
Based on degree of differentiation, sometimes # of mitoses or architectural features.
Tumor staging
Based on size of primary tumor, extent of lymph spread, presence of distant metastases.
Yearly cancer deaths worldwide
7.6 million.
Environmental factors
Smoking, Alcohol consumption, reproductive history, Diet, infectious agents, occupational hazards.
Acquired conditions that predispose to cancer.
Chronic inflammation, immunodeficiency status, precursor lesions.
4 Classes of Cancer Genes
Oncogenes
Tumor Suppressor genes
Apoptosis regulatory genes
Regulation between tumor and host genes
Oncogene
Genes that induce a trnasformed phenotype that promotes cell growth. They are mutated or overexpressed versions of normal genes (which are called Proto-oncogenes).
Proto-oncogenes
Genes which participate at some level in signaling pathways that drive proliferation, such as growth factors, GF receptors, signal transducers, transcription factors, or cell cycle components.
Oncoproteins
Encoded by oncogenes, they are usually constitutively active. As a result they endow cells with self sufficiency in growth.
RAS
Very common mutation. Activated by point mutations which interfere with breakdown of GTP, which inactivates RAS. RAS is trapped in activated form, cell continuously proliferates.
ABL oncogene
Normal ABL has tyrosine kinase activity that is dampened by internal negative regulatory domains. In Chronic myeloid leukemia, the ABL gene is translocated from Chromosome 9 to Chromosome 22, and fuses with the Breakpoint Cluster Region (BCR). Constitutive tyrosine kinase activity starts, activating all signals downstream of RAS.
MYC oncogenes
Activates the transcription of other genes. It can activate CDKs, and genes that control pathways that produce the building blocks of cell growth and division. Burkitt’s Lymphoma (B-cell tumor) is caused by a chromosomal 8;14 translocation of MYC.
Cyclin-dependent Kinases.
Orchestrate the progression of the cell cycle by binding to cyclin. The complexes they form target crucial proteins that drive the cell cycle forward.
CDK inhibitors (CDKIs)
Silence CDKs and negatively regulate the cell cycle.
D-CDK4, D-CDK6, E-CDK2
Regulate the G1 to S transition by phosphorylating Rb protein.
A-CDK2 and A-CDK1
Active in the S phase.
B-CDK1
Regulates G2 to M transition
G1 to S Checkpoint
Tightly regulated transition period in the cell cycle. Once passing this checkpoint, cells are committed to cell division. Defects are important to cancer.
Gain-of-function Mutations
Involving CDK4 or D cyclins can cause neoplasms.
Loss of function mutations
Involve CDKI becoming disabled or silences seen in many malignancies.
Tumor suppressor genes
Can apply the brakes to cell proliferation. Disruption of these genes mimics the effects of oncogenes.
RB
(Retinoblastoma gene)
Key negative regulator of the cell cycle. First tumor suppressor gene to be discovered. RB has a two hit hypothesis. One copy of defective RB is transmitted genetically, one is a result of random mutation.
RB is not just involved in retinoblastomas, but can be active in other cancers as well. Patients with familial retinoblastoma at high risk of developing osteosarcomas, and soft-tissue sarcomas.
TP53
P53-encoding tumor suppressor gene. Most commonly mutated in human cancer. p53 protein normally prevents neoplastic transformation by activation of quiescence and senescence or triggering apoptosis. P53 plays essential role in maintaining integrity of the genome.
If p53 is not functioning, cells can undergo malignant transformation.
70% of human cancers have a defect in p53.
Li-fraumeni syndrome
Inheritance of a mutant TP53 allele. Predisposes individuals to develop malignancies, x25 times higher chance of malignancy by age 50.
BCL2
Anti-apoptotic gene. In certain lymphomas this gene can be translocated to an active area, allowing production of BCL-2 family proteins which block the mitochondrial pathway of apoptosis.
