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
Cell Cycle Regulation
o Upon proliferation stimulation, a cell enters the cell cycle
o Cyclins and cylin-dependent kinases (CDKs) are important to the cycle
o Transition from G1 to S phase is particularly important checkpoint
o Most common cancerous mutations affect proteins involved in G1-S transition
Overexpression of cylcin D (breast, esophagus, liver cancers, lymphomas)
Amplification of CDK4 (melanomas, sarcomas, glioblastomas)
Tumor Suppressor Genes - Proliferative Breaks
o Encode proteins, which normally inhibit cell proliferation or stimulate apoptosis upon cell damage; often inactivated in cancer cells by mutations, truncation, deletions or methylation (epigenetics), leading to uncontrolled growth and accumulation /propagation of defective cells
o Mutations of tumor suppressor genes are usually RECESSIVE 2 alleles must be altered to lose their function
o Inherited mutations of the tumor suppressor genes contribute to familial cancers
Hereditary cancers develop earlier in age than sporadic malignancies and often arise in multiple locations
Oncogenes are not typically associated with heritable cancers because a fetus is less likely to develop properly
Tumor Suppressor Genes - Retinoblastoma
– encodes DNA-binding protein; controls G1-S checkpoint – RECESSIVE
o First tumor suppressor identified and served as foundation for the “Two Hit Hypothesis”
o Retinoblastoma - pediatric tumor developing in retina due to deletion of RB tumor suppressor gene; Treatment: removing the eye (enuclation)
o In quiescent cells, active unphosphortylated RB prevents progression into S-phase genes
o Upon growth factor stimulation, RB protein is inactivated by phosphorylation, which allows progression of cell cycle
o Deregulation of G1-S checkpoint by mutations has been found in majority of cancers
Familial vs. Sporadic Form of Retinoblastoma
o Sporadic form – both mutations in RB gene are acquired AFTER birth; frequency of the tumor is relatively low; usually develops later in life
o Familial form – one mutation in RB protein is inherited; therefore, only one additional mutation has to occur in one of the retinal cells MORE common
Frequency of retinoblastoma is very high and the tumors often arise bilaterally
Cells in the retina do not undergo apoptosis as well as other cells
Tumor Suppressor Genes - Adenomatous Polyposis Coli (APC)
o Controls proliferation and adhesion of cells through interactions with beta-catenin – signaling molecule in WNT pathway
o In absence of WNT, APC binds beta-catenin and stimulates its degradation
o Upon WNT stimulation, APC releases beta-catenin; beta-catenin translocates to the nucleus and activates genes promoting cell cycle
o Germline mutations of APC gene development of multiple benign tumors (polyps) in colon;
Transform to malignant cancer nearly 100% of time; associated w/ loss of 2nd APC allele
o APC mutations also occur in majority of sporadic colorectal cancers
Tumor Suppressor Genes - p53
– believe this mutation occurs first and is responsible for the error leading to malignancy; LATER an oncogene mutation results in cancer
o p53 controls cell proliferation and apoptosis at the G1 S phase transition
“detects” cellular stress and prevents propagation of damaged cells
o p53 is one of most commonly mutated genes in human cancer (over 70%)
o Normally p53 is bound to MDM2 gene, which causes its degradation and short half-life
o Upon cellular stress, p53 is released from the complex with MDM2, which increases its half-life
Active p53 is a tetrameric transcription factor that stimulates transcription of CDK inhibitor p21 which leads to G1 cell cycle arrest and apoptosis
• Simultaneously DNA repair systems are activated (GADD45) if repair is successful then cell resumes normal function
Mutations/loss of p53 accumulation and propagation of mutated and damaged cells allows survival of the cells with overexpressed or deregulated mitogenic factors
p53tumor-associated mutations very often affect DNA-binding domain (DBD)
Types and Consequences of p53 Mutations
o Loss of function – mutant p53 not functional but doesn’t interfere with actions of wild type allele
Least dangerous - Requires additional mutation to lead to symptoms/disease
o Dominant negative mutant – mutant p53 forms a complex with the wild type allele and prevents its binding to the target gene promoters
o Gain of function (most dangerous) – mutant p53 binds to different DNA sequences and activates different target genes, which can lead to stimulation of cell proliferation instead of cell cycle arrest and apoptosis
Li Fraumeni Syndrome
– germline mutations in p53 gene – LFS-DOMINANT
o Very high penetrance in people with the mutation
o Elevated risk of development of number of tumors often at younger age and multiple locations (soft-tissue sarcomas, osteosarcomas, brain tumors, breast cancer)
Tumor Suppressor Genes - Breast Cancer Predisposition Genes
o Function: Encode nuclear proteins involved in response to DNA damage and DNA repair
o BRCA1 – germline mutation cause increased risk of breast & ovarian cancers (85% & 50%)
Mutations have been found in 40-50% of families with multiple breast cancer cases
No BRCA1 mutations have been described in sporadic breast cancers; while incidence in sporadic ovarian cancers is only 5%
o BRCA2 – germline mutation cause increased risk of breast cancer (80%) in MEN & women
Tumor Suppressor Genes - DNA Repair Genes
o DNA repair genes are NOT directly involved in cell cycle regulation
o Lack of DNA repair activity leads to genetic instability and facilitates mutations in other genes such as tumor suppressors and oncogenes that will directly affect the cell cycle
o Hereditary nonpolyposis colorectal cancer (HNPCC) – associated with defects of DNA mismatch repair genes; NO benign polyps present, making it extremely dangerous
o Xeroderma pigmentosum – increased risk of UV-induced skin cancers due to the defects in the nucleotide excision repair; increased number of UV-cross-linked residues
Familial Tumors Caused by Mutations in Oncogenes
Anaplastic Lymphoma Kinase (ALK ) – receptor tyrosine kinase ONLY expressed in CNS/PNS neuronal tissue
o Germline activating mutations of ALK have been associated with familial neuroblastoma, which segregates as autosomal-dominant disease with limited penetrance
o Exception to the rule that oncogenes are not associated with familial cancer
MicroRNAs
– important regulatory molecules – heavily associated in the differentiation process
o Bind to mRNA and either cause degradation or block translation
o Oncogenic miRNAs target tumor suppressors AND tumor suppressor miRNAs target oncogenes
Alteration of their balance can trigger/facilitate malignant transformation
Deregulation of Apoptotic Mechanisms
– leads to propagation of damaged, mutated cells
Genes promoting apoptosis can be downregulated/inhibited (ex: caspases)
Genes inhibiting apoptosis can be upregulation/stimulated (ex: BCL2)
o Extrinsic mechanism – receptors on cell membrane get activated and induce apoptosis
o Intrinsic mechanism – triggered by things like hypoxia, overexpression of oncogenes, and DNA damage (all of which activate the p53 pathway)
Telomeres and Telomerase
o Due to shortening of telomeres, most normal cells have a capacity of 60-70 replications
After this the cells enter a nonreplicative senescence (stop proliferating) or apoptosis
o Telomerase - enzyme that maintains normal telomere length preventing their senescence/death
Stem cells AND most cancers - telomerase is upregulated allows unlimited cell divisions
