Cancer I Flashcards
Silent vs. Normal Gene
- Silent gene – genes are present in the nucleus but they are not active (no mRNA produced)
- Normal gene – genes are actively transcribed into mRNA template for protein synthesis
Gene Overexpression vs. Amplification
- Gene Overexpression – “overactive”; produce high levels of mRNA results in high level of proteins
- Gene Amplification – multiple copies of the gene are present in the nucleus; each of them is active and produces mRNA resulting in high levels of protein
Naming and Types Cancers
• Prefix – refer to location of cancer
• Suffix refers to benign (-oma) or malignant (-carcinoma, -sarcoma)
• Cancer – malignant neoplasia
o Carcinomas – cancer of epithelial origin; most common form of cancer
o Leukemias – cancer of bloodstream
o Lymphomas – cancer of lymph nodes
o Sarcomas – cancer of mesenchymal origin
Stages of Abnormal Growth (Hyperplasia, dysplasia, anaplasia, neoplasia)
o Hyperplasia – increase in number of normal cells o Dysplasia – some cellular and nuclear changes leading to loss of cell uniformity and abnormal tissue architecture o Anaplasia – undifferentiated cells, variable in size and shape; numerous and atypical mitoses, lack of organized tissue architecture; will become invasive/cancerous Ex: rhabdomyosarcoma of skeletal muscle o Neoplasia (tumor) – abnormal tissue growth; result of loss of responsiveness to growth control signals; does not necessarily mean MALIGNANT/CANCER (ex: fibroids)
Benign Tumor
• Benign Tumor – well-differentiated cells with preserved specialized features of the parent cells
o Usually well demarcated, often encapsulated masses, no invasion of the surrounding tissue
o No distant metastases
o Ex: uterine fibroids (leiomyoma) – develop from smooth muscle
Malignant Tumor
• Malignant Tumor – lack of differentiation, anaplasia
o Locally invasive, infiltrating surrounding tissues
o Frequently present distant metastases
Normal Growth Regulation and Areas Proliferative Growth
• Normal Growth Regulation – most of the cells are quiescent; cell proliferation is limited to certain types of cells and processes, such as:
o Bone marrow myeloblasts; immune cells; epidermal cells; epithelial cells; regenerating tissues
o Cell proliferation tightly regulated process involving factors stimulating/inhibiting cell divisions
o Cell damage or perturbation in cell cycle leads to cell death (apoptosis)
Features of Malignant Cancer Cells
o Self-sufficiency in growth signals o Insensitivity to growth-inhibitory signals o Evasion of apoptosis o Limitless replicative potential o Sustained angiogenesis o Ability to invade and metastasize o Evasion of host immune response
Normal Growth Mechanism
growth factors cell surface receptors signal transducing proteins that send signal from cell surface to nucleus via phosphorylation cascade transcription factors inside nucleus gene expression of previously unexpressed proteins gene products required for cell division, cell cycle progression, & proliferation
Proto-oncogenes vs. Oncogenes
• Proto-oncogenes – encode proteins, which normally stimulate cell proliferation
o Mutations of proto-oncogenes usually arise somatically in the tumor cells and are DOMINANT
o Encode growth factor, growth factor receptor, signal transduction molecules, transcription factor
• Oncogenes (in cancers) – gain-of-function alterations/mutations of proto-oncogenes resulting from point mutations, chromosomal rearrangements/translocations, gene amplification, and over-expression due to changes in regulatory elements
Proto-oncogenes - Growth Factors
– overexpression of autocrine growth factors leading to overstimulation of proliferation
o Gain independence from host cells & stimulate the growth of nearby cells via paracrine signaling
o Platelet-derived growth factor (PDGF) – in glioblastomas
o Transforming growth factor alpha (TGFalpha) – in sarcomas
Proto-oncogenes - Growth Factor Receptors
- extracellular part = control; intracellular part = activation
o Mutated or truncated forms of the receptors - intracellular domain constitutively active
Epidermal growth factor (EGF) receptor ERBB1 is truncated in glioblastoma
o Overexpression of growth factor receptors
ERBB1 in squamous cell carcinomas of the lung; ERBB2 (HER2) in breast cancer
Proto-oncogenes - Signal-Transducing Proteins - RAS
– encodes p21 G-protein
Point mutations changing amino acids in the pocket binding GTP and region essential for GTP hydrolysis lead to constitutive activation of RAF-MAPK mitogenic cascade
Mutant RAS proteins cannot release or hydrolyze GTP, causing constitutive activation of RAF-MAPK cascade
RAS mutations are most common abnormalities in human cancer
• Particularly high incidence in colon and pancreatic cancers
Proto-oncogenes - Signal-Transducing Proteins - ABL
– non-receptor tyrosine kinase that normally promotes apoptosis
Chronic myeloid leukemia – ABL gene is translocated from chromosome 9 chromosome 22 where it fuses with part of breakpoint cluster region (BCR) gene; aberrant chromosome 22 is designated the Philadelphia chromosome
Normal ABL is localized to the nucleus; abnormal BCR-ABL is in cytoplasm
Stimulates kinase activity that phosphorylates proteins involved in proliferation pathways
Proto-oncogenes - Nuclear Transcription Facters
o Stimulate expression of several growth-related genes, such as cyclin-dependent kinases (CDKs)
o MYC – most commonly involved in human cancer
C-MYC = normal version of gene
Burkitt lymphoma – overexpressed due to translocation from chromosome 8 chromosome 14, in close proximity to an Ig gene
Breast, lung and other cancers – overexpressed due to gene amplification
• Common in neuroblastoma (N-MYC) and small cell cancer of lung (L-MYC)
• Neuroblastoma has 2 forms; mainly affects children and infants
o Aggressive phenotype that requires immediate treatment/chemotherapy
MYC amplification is diagnostic marker
o Less aggressive phenotype that spontaneously regresses at one year of age and does NOT require treatment