Carcinogenesis

Carcinogenesis is the development of cancer by transforming healthy cells into cancer cells. This complex process occurs because of mutations in DNA that prevent the normal process of cell division. Normal cells have programmed cell death, but cancer cells proliferate without regulation. The genetic changes that cause cancer may occur in reproductive cells of the ova and sperm and propagate to progeny. Somatic changes are acquired during an individual’s lifetime because of exposure to carcinogenic chemicals, tobacco, radiation, and other factors. Mutations in oncogenes that promote cell growth and tumor suppressor genes that reduce cell growth are important mechanisms in the dysregulation of cell division and lead to cancer. Cancers are classified by their cell type and their location.

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DNA-Damaging Agents

Overview

  • Genetic mutations are considered the primary cause of cancer.
  • Numerous mutations are required.
  • Cell growth dysregulation → uncontrollable cell growth
  • > 1 in 3 cases of cancer are attributed to a modifiable risk factor (e.g., smoking)
  • Predispose to cancer:
    • Chemical exposure (including tobacco and alcohol)
    • Radiation exposure (sunlight, x-rays)
    • Infections (e.g., human papillomavirus)

Chemical carcinogens

  • Benzene and toluene: found in gasoline and cigarettes
  • Ethanol
  • Cigarettes (many carcinogenic chemicals)
  • Vinyl chloride
  • Nitrosamines: found in cured meats and smoked foods → gastric cancer
  • Asbestos: found in insulating materials:
    • Lung cancer
    • Mesothelioma
    • Renal cell carcinoma
  • Arsenic:
    • Squamous cell cancer of the skin and lung
    • Angiosarcoma of the liver
  • Silica: associated with sandblasting → lung cancer
  • Chromium and nickel → lung cancer

Radiation

  • Nonionizing radiation:
    • Ultraviolet B (UVB) light → skin cancer
    • Produces pyrimidine dimers in DNA leading to transcriptional errors; also, mutations of oncogenes and tumor suppressor genes
  • Ionizing radiation:
    •  X-rays: associated with hematologic malignancies
    • Atomic bomb → leukemias, thyroid cancer
    • Uranium → lung cancer
    • Radium → osteosarcoma
    • Gamma rays:
      • Considered the most dangerous form of ionizing radiation
      • Can affect tissue from the skin to deep structures like bone marrow
    • Alpha particles in radon gas → lung cancer

Infections

  • DNA viruses: 
    • Human papillomavirus: cervical carcinoma 
    • Epstein-Barr virus: infects B cells and epithelial cells of nasopharynx via CD21 
      • Burkitt lymphoma 
      • B-cell lymphoma
      • Hodgkin disease
      • Nasopharyngeal carcinomas
    • Hepatitis B: hepatocellular (liver) carcinoma
  • RNA viruses: 
    • Hepatitis C: hepatocellular (liver) cancer 
    • Human T-cell leukemia virus type 1: infects CD4+ T cells to produce T-cell leukemia/lymphoma
  • Bacteria: Helicobacter pylori
    • Linked to gastric carcinomas and lymphomas (B cell)
    • Can be reversed with triple-therapy treatment before developing into lymphoma
Mechanisms of carcinogenesis due to carcinogens causing dna damage

Mechanisms of carcinogenesis due to carcinogens causing DNA damage

Image by Lecturio. License: CC BY-NC-SA 4.0

Pathogenesis

Overview

  • Cancer is a problem with cellular dysfunction; it does not have to be lethal genetic damage.
  • Occurs in a multistep process: exposure to carcinogen → genes involved in cell growth, differentiation, and survival activated
  • Carcinogens lead to the development of mutations that are passed along to future generations of cells.
  • These mutations lead to faster cell proliferation, further mutations, and eventually, metastasis (spread of cancer to other locations of the body via the hematologic or lymphatic system).

Cellular changes

  • Gradual changes in cell properties accumulate with genetic changes that occur over a long period of time.
  • Clonal expansion of a single genetically damaged precursor cell → tumor
  • Typical cellular changes that accompany the development of cancer:
    • Hyperplasia (increase in the number of cells)
    • Increasing variation in cell and nuclear size and shape
    • Loss of tissue structure
  • Dysplasia: abnormal proliferation with loss of normal structure of cells 
    • Severe dysplasia: carcinoma in situ
    • Carcinoma in situ describes a state in which there are dysplastic cells that have not migrated or invaded other tissue.
  • The transformation from a normal cell to a cancer cell requires many steps that prove advantageous to growth:
    • Self-sufficiency in growth signaling
    • Insensitivity to anti–growth signaling
    • Evade apoptosis
    • Limitless replicative potential
    • Sustained angiogenesis
    • Tissue invasion and potential for metastasis
Pathophysiology of cancer carcinogenesis

Pathophysiology of cancer

Image: “Mechanisms contributing to evasion of apoptosis and carcinogenesis” by Wong, R.S. License: CC BY 2.0

Regulatory Genes

There are 4 classes of normal regulatory genes that are often damaged.

  • Oncogenes (e.g., c-myc in Burkitt lymphoma):
    • Promote cell growth and division
    • Increased expression → carcinogenesis (uncontrolled cell growth)
    • Allow for cells to avoid programmed cell death (apoptosis)
    • Categorized according to their cellular function:
      • Growth factor: leads to cell proliferation
      • Tyrosine kinase: passes along cell signals
      • Guanosine triphosphatase (GTPase): passes along cell signals
      • Transcription factor: induces cell growth and division
    • Proto-oncogene: nonfunctional version of an oncogene:
      • Up-regulation (a type of mutation that increases expression) in a proto-oncogene allows for the gene to become an oncogene.
      • With this mutation, an oncogene promotes cell growth.
  • Tumor suppressor genes: 
    • Inhibit cell division
    • Decreased expression → carcinogenesis
    • Normally function to prevent uncontrolled cell growth
    • Mutation → uncontrolled cell growth
    • Tumor suppressor genes are categorized:
      • Caretaker gene: involved in DNA repair
      • Gatekeeper gene: regulate cell growth
  • Genes that regulate apoptosis:
    • Significant mutation → no programmed cell death 
    • Mutations are passed along to future cell lines.
    • p53 is a tumor suppressor gene that promotes apoptosis when it is functioning normally
      • After loss-of-function mutation, p53 does not arrest the cell cycle
      • p53 is implicated in nearly half of all known cancers.
  • Genes involved in DNA repair

Cancer Subtypes

Type of cell

  • Carcinoma: derived from epithelial cells 
  • Sarcoma: derived from connective tissue
  • Lymphoma and leukemia: derived from bone marrow
  • Germ cell tumor: derived from pluripotent cells

Common cancers

  • Osteosarcoma: bone cancer of mesenchymal origin
  • Glioblastoma: aggressive brain cancer
  • Breast cancer
  • Retinoblastoma: intraocular cancer arising from the retina
  • Colorectal cancer
  • Pancreatic cancer
  • Prostate cancer
  • Hematopoietic cancer:
    • AML 
    • CLL
    • CML 
    • Hodgkin lymphoma
  • Melanoma: skin cancer arising from melanocytes
  • Lung cancer:
    • Small-cell lung cancer
    • Non–small-cell lung cancer:
      • Adenocarcinoma
      • Squamous cell carcinoma

Clinical Relevance

  • Breast cancer: 2nd most common cause of cancer-related death in women after lung cancer. The most common histologic type of breast cancer is infiltrating ductal carcinoma. Screening with mammography is recommended, and diagnosis is made by biopsy. Treatment relies on surgery, radiation, and systemic therapies (e.g., chemotherapy, endocrine therapy).
  • Prostate cancer: most common cancer in men. Most often, prostate cancer is slow-growing, and for this reason, there is disagreement about the need for routine screening. Risk factors are older age, African American or Caribbean heritage, and family history of prostate cancer. The preferred method for screening is PSA testing. Diagnosis is confirmed with biopsy. 
  • Lung cancer: Bronchogenic carcinoma, or lung cancer, is a malignancy that arises from the epithelial lining of the bronchus or bronchiole. Lung cancer is the most common cancer death in the United States. Tobacco smoking is the most important risk factor for disease, and smoking cessation decreases the risk of lung cancer. A patient may present with cough, weight loss, hemoptysis, or chest discomfort. Chest CT is used for screening in patients with an extensive smoking history. Diagnosis is with biopsy. Treatment may involve surgery, radiation, and chemotherapy.

References

  1. Botelho, M.C., et al. (2014). Carcinogenesis. In Wexler, P. Ed., Encyclopedia of Toxicology, 3rd ed.
    Elsevier, pp. 713–729. https://www.sciencedirect.com/science/article/pii/B9780123864543003717
  2. National Cancer Institute: National Institutes of Health. (2021). What is cancer? Retrieved May 6, 2021, from https://www.cancer.gov/about-cancer/understanding/what-is-cancer 
  3. Dunn, L., Rudin, C.M. (2021). Head and neck squamous cell carcinogenesis: molecular and genetic alterations. UpToDate. Retrieved July 20, 2021, from https://www.uptodate.com/contents/head-and-neck-squamous-cell-carcinogenesis-molecular-and-genetic-alterations
  4. Frucht, H., Lucas, A.L. (2021). Molecular genetics of colorectal cancer. UpToDate. Retrieved July 20, 2021, from https://www.uptodate.com/contents/molecular-genetics-of-colorectal-cancer

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