Cancer Biology and Epigenetics

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