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Questions and Answers
What factors regulate angiogenesis?
p53, RAS, MYC, MAPK signaling
Which enzymes mediate basement membrane and interstitial matrix degradation in invasion and metastasis?
Tumor antigens are presented on the cell surface by MHC class II molecules.
False
Defects in the homologous recombination DNA repair system lead to syndromes such as Bloom syndrome, ataxia-telangiectasia, and Fanconi __________.
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Match the microbial agent with the associated cancer type:
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What is neoplasia?
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How are benign tumors typically named?
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Benign tumors are generally well-differentiated and composed of cells resembling mature normal cells.
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__________ is the spread of a tumor to sites that are physically discontinuous with the primary tumor.
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Match the following tumor nomenclature with their meanings:
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What is the basis for the grading of cancer?
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How are cancers classified based on grading?
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What is the basis for the staging of cancers?
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What does the 'T' stand for in the TNM system for cancer staging?
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Immunohistochemistry can help categorize undifferentiated malignant tumors.
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Flow cytometry can rapidly measure several individual cell characteristics, such as membrane antigens and DNA content of tumor cells.
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Match the tumor marker with the associated cancer:
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What determines which genes are silenced and which are expressed in tumourigenesis?
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What is the effect of epigenetically silencing a tumour suppressor gene?
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Which genes cause excessive cell growth and proliferation even without external growth factors in tumour cells?
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Match the following tumor components with their characteristics:
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Imatinib is a drug used to treat cancer by targeting nonreceptor tyrosine kinases.
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What is the role of the TP53 gene in cancer?
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Study Notes
Neoplasia
- Neoplasia refers to "new growth" or a collection of cells and stroma composing new growths, also referred to as neoplasm or tumor.
- This is different from the tumor described in cardinal signs of inflammation as swelling.
- Cancer is the common term for all malignant tumors.
Neoplasia: Definition
- A neoplasm or tumor is defined as a genetic disorder of cell growth, triggered by acquired or less commonly inherited mutations affecting a single cell and its colony progeny.
Neoplasia: Nomenclature
- All tumors, benign and malignant, are composed of two components:
- Neoplastic cells that constitute the tumor parenchyma.
- Reactive stroma made up of connective tissue, blood vessels, and the cells of the adaptive and innate immune system.
- The parenchyma of the tumor determines its biologic behavior and is the component from which the neoplasm derives its name.
- Benign tumors bear the suffix "-oma" to the cell of origin, e.g. fibroma, lipoma, and meningioma.
Characteristics of Benign and Malignant Tumors
- Differences between benign and malignant tumors can be discussed under the headings:
- Differentiation and anaplasia
- Rate of growth
- Local invasion
- Metastasis
Differentiation and Anaplasia
- Differentiation refers to the extent to which parenchymal cells resemble comparable normal cells, both morphologically and functionally.
- Well-differentiated tumors are composed of cells resembling the mature normal cells of the tissue of origin.
- Poorly or undifferentiated tumors have primitive-appearing, unspecialized cells.
- Benign tumors are generally well-differentiated, while malignant tumors range from well-differentiated to undifferentiated.
- Anaplasia, or lack of differentiation, is a hallmark of malignant transformation.
Rate of Growth
- Generally, most benign tumors grow slowly over a period of years, while most cancers grow rapidly, sometimes at an erratic pace.
Local Invasion
- Nearly all benign tumors grow as cohesive expansile masses that remain localized, with a rim of compressed connective tissue.
- Malignant tumors, on the other hand, grow with progressive infiltration, invasion, and destruction of surrounding tissue.
Metastasis
- Metastasis is the spread of a tumor to sites that are physically discontinuous with the primary tumor.
- Metastasis unequivocally marks a tumor as malignant, as benign neoplasms do not metastasize.
- With few exceptions, all cancers can metastasize.
- The more aggressive, rapidly growing, and larger the primary neoplasm, the greater the likelihood it has or will metastasize.
Epidemiology
- The worldwide cancer rate is increasing, with incidence rates stabilized in men but increasing in women.
- The incidence rate is low in developing countries due to poor access to health facilities and poor record keeping.
- The actual incidence rate of cancer is increasing in developing countries compared to advanced countries.
- Common cancers in females include breast, lung, and colon/rectum cancer.
- Common cancers in males include prostate, lung, and colon/rectum cancer.
Environmental Factors
- Environmental influences are the dominant risk factors for most cancers, including:
- Obesity
- Alcohol abuse
- Diet
- Smoking
- Promiscuity
- Cancer occurs in certain age groups, with death rates highest in women between 40-79 years and in men between 60-79 years.
Molecular Basis of Cancer
- Nonlethal genetic damage, clonal expansion of a single precursor cell with genetic damage, and four classes of genes that mutate contribute to the development of cancer.
- The four classes of genes that mutate are:
- Proto-oncogenes
- Tumor suppressor genes
- Programmed cell death genes
- DNA repair genes
- Mutations that contribute to the acquisition of cancer hallmarks are referred to as driver mutations.
- The first mutation that starts the process is the initiating mutation, which is maintained in all daughter cells.
Oncogenes
- Oncogenes are mutated genes that cause excessive cell growth, even in the absence of growth factors and other growth-promoting external cues.
- They are mutated or overexpressed proto-oncogenes that produce oncoproteins which are constitutively active and resistant to external control, leading to cell proliferation.
Cell Cycle and Growth Control
- Self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, and altered cellular metabolism are hallmarks of cancer.
- Growth factors, growth factor receptors, downstream components of the receptor tyrosine kinase signaling pathway, and transcription factors all contribute to the development of cancer.
- Examples of oncogenes include:
- RAS
- BRAF
- PI3K
- JAK/STAT
- MYC
Insensitivity to Growth Inhibition
- Tumor suppressor genes, such as TP53, apply brakes to cell proliferation and are often inactivated in cancer.
- The "two-hit" hypothesis of oncogenesis in RB explains how loss of function in both alleles of the RB gene leads to retinoblastoma.
- TP53 is the most frequently mutated gene in human cancers, and its inactivation can lead to uncontrolled cell growth and cancer.Here are the study notes for the text:
Cancer Biology
- Loss of p53 function: leads to unrepaired DNA damage, driver mutations in oncogenes and cancer genes, and malignant transformation
- TP53 mutations: lead to a mutator phenotype, where cells accumulate mutations and become cancerous
- Tumor suppressor genes: APC, E-Cadherin, CDKN2A, PTEN, VHL, and others, which normally prevent cancer by regulating cell growth and division
Cellular Metabolism
- Warburg metabolism: a form of growth-promoting metabolism that favors glycolysis over oxidative phosphorylation, resulting in the production of macromolecules
- Macromolecules produced: nucleotides, amino acids, and lipids
Evasion of Cell Death
- Apoptosis: programmed cell death that can be initiated through intrinsic or extrinsic pathways, leading to cell destruction
- Anti-apoptotic mechanisms: cancer cells may overexpress BCL2 or inactivate p53 to evade apoptosis
Limitless Replicative Potential
- Cancer stem cells: cells that may arise from normal stem cells or mature cells that acquire stem-like properties, allowing them to proliferate indefinitely
- Telomerase reactivation: allows cancer cells to maintain their telomeres and divide indefinitely
Angiogenesis
- Vascularization of tumors: essential for tumor growth, regulated by the balance between angiogenic and anti-angiogenic factors
- VEGF: a pro-angiogenic factor produced by tumor cells, which can be inhibited by anti-angiogenic therapy
Invasion and Metastasis
- Steps of invasion: loosening of cell-cell contacts, degradation of ECM, attachment to novel ECM components, and migration of tumor cells
- Loss of E-cadherin: leads to loss of cell-cell contacts and invasion
Evasion of Immune Surveillance
- Immune evasion mechanisms: include selective outgrowth of antigen-negative variants, loss of histocompatibility antigens, and immunosuppression
- Cancer antigens: include products of mutated proto-oncogenes, tumor suppressor genes, and viral antigens
Genomic Instability and Malignancy
- Inherited mutations: in genes involved in DNA repair systems increase the risk of cancer
- Microsatellite instability: a hallmark of some cancers, including colorectal cancer
Carcinogenesis
- Chemical carcinogens: directly damage DNA, leading to mutations and cancer
- Radiation carcinogenesis: ionizing radiation causes chromosome breakage, translocations, and point mutations
- Viruses: some viruses, such as HTLV-1, HPV, and HBV, can cause cancer through various mechanisms
Clinical Aspects of Neoplasia
- Local and hormonal effects: cancers can produce hormones, leading to manifestations such as Cushing's syndrome
- Cachexia: a wasting syndrome common in cancer patients, caused by soluble factors such as inflammatory cytokines
- Paraneoplastic syndromes: rare syndromes caused by cancer, which can mimic metastatic disease
Grading and Staging of Tumors
- Grading: based on the degree of differentiation and number of mitoses
- Staging: based on the size of the primary lesion, regional lymph node involvement, and presence of metastases
- TNM system: a widely used system for staging cancer
Laboratory Diagnosis of Cancer
- Immunohistochemistry: uses specific antibodies to identify cell products or surface markers
- Flow cytometry: measures cell characteristics such as membrane antigens and DNA content
- Molecular diagnostics: uses DNA sequencing, PCR, and other techniques to diagnose cancer and detect minimal residual disease.### Tumor Markers (Hormones)
- Human chorionic gonadotropin is associated with trophoblastic tumors and non-seminomatous testicular tumors
- Calcitonin is associated with medullary carcinoma of the thyroid
- Catecholamine and metabolites are associated with pheochromocytoma and related tumors
- Ectopic hormones are associated with tumors of the paraneoplastic syndrome group
Tumor Markers (Isoenzymes)
- Prostatic acid phosphatase is associated with prostate cancer
- Neuron-specific antigen is associated with small cell cancer of the lung and neuroblastoma
Tumor Markers (Specific Proteins)
- Immunoglobulins are associated with multiple myeloma and other gammopathies
- Prostate-specific antigen is associated with prostate cancer
Tumor Markers (Mucins & Other Glycoproteins)
- CA-125 is associated with ovarian cancer
- CA-19-9 is associated with colon and pancreatic cancer
- CA-15-3 is associated with breast cancer
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Description
This quiz covers the evolution of tumors, mutations, and epigenetic changes that influence cancer therapy and tumorigenesis.
