Cancer Biology Notes

• Cancer is a disease arising from abnormalities in cell function, characterized by uncontrolled cell growth and the potential to invade other parts of the body.

• It's a disease where abnormal tissues grow and spread unrestrained throughout the body, disrupting normal tissue function and potentially leading to organ failure.

• Almost half of the UK population will eventually develop cancer, making it the second leading cause of death, highlighting the importance of early detection and treatment.

• Understanding cancer biology requires detailed knowledge of normal cell behavior, including cell signaling, DNA replication, and programmed cell death (apoptosis).

Classification of Cancers

• Cancers are grouped into different categories depending on the cell type involved:

  • Carcinoma: Arises from epithelial cells that cover external and internal surfaces; these are the most common types of cancer.

  • Examples: Lung, Breast, Colon. These often spread through lymphatic vessels.

  • Sarcoma: Arises from cells of supporting tissues, which are less common than carcinomas.

  • Examples: Bone (osteosarcoma), Cartilage (chondrosarcoma), Fat (liposarcoma), Connective tissue, Muscle (rhabdomyosarcoma).

  • Leukaemia & Lymphoma: Arise from blood and lymphatic cells, affecting the body's ability to fight infection.

  • Examples: Blood (acute myeloid leukemia), Bone marrow, Lymph nodes (Hodgkin's lymphoma), and other lymphoid organs

Tumour Formation

• Tumor formation involves:

  • Uncontrolled proliferation, where cells divide excessively without proper regulation.

  • Disrupted balance between cell division and cell differentiation, leading to an accumulation of immature cells.

• Normal Growth: Balanced proliferation and differentiation, maintaining tissue homeostasis.

  • Example: Skin

  • Outer skin surface with shedding of dead cells.

  • Squamous cells.

  • Cell migration from the basal layer (dividing cells).

  • Basal lamina.

  • Underlying tissue.

• Tumor Growth: Imbalanced proliferation and differentiation, resulting in tumor mass.

  • Example: Skin - Carcinoma

  • Underlying tissue involvement, indicating invasive growth.

The Genetic Basis of Cancer

• Genetic mutations cause abnormalities in cell function observed in cancer cells, disrupting normal cellular processes.

• Mutations in genes controlling cell proliferation and division contribute to cancer development; these genes are critical for maintaining genomic stability.

• Two main gene classes are affected:

  • Oncogenes, which promote cell growth and division when activated.

  • Tumour suppressor genes, which inhibit cell growth and division, preventing tumor formation.

Oncogenes

• Proto-oncogenes regulate cell growth, proliferation, and gene expression; they are essential for normal cell function.

• Mutation in a proto-oncogene can result in an oncogene, leading to uncontrolled cell growth.

• Oncogenes drive unrestrained cell proliferation and confer malignant characteristics to cells, contributing to cancer development.

• Gain of function mutation, where the gene product has increased activity or new functions.

• Example: RAS gene, which is involved in cell signaling pathways.

Proto-oncogene to Oncogene Conversion:

• (a) Point mutation: Single nucleotide substitution causing a single amino acid substitution in the protein encoded by the normal proto-oncogene, altering its function.

  • Example: RAS oncogene codes for an abnormal form of Ras protein that drives progression through the S phase of the cell cycle.

  • Associated cancers: Bladder, Colon, Lung, Pancreas, Thyroid.

• (b) Gene amplification: Increased number of copies of a proto-oncogene; the protein encoded is produced in excessive amounts, although the protein is normal, leading to increased cell signaling.

  • Example: ERBB2 gene codes for a growth factor receptor.

  • Associated cancers: Breast, Ovarian. This amplification leads to excessive cell proliferation.

• (c) Chromosomal translocations: Part of one chromosome is removed and joined to another chromosome, disrupting normal gene regulation.

  • Example: Proto-oncogene MYC is translocated from chromosome 8 to 14 and overexpressed. The MYC gene encodes a transcription factor that stimulates cell proliferation.

  • Associated cancer: Burkitt’s lymphoma. The translocation causes the MYC gene to be under the control of a highly active promoter.

• (d) Local DNA rearrangements: Insertions, deletions, inversions, or transpositions of proto-oncogenes, altering their expression or function.

  • Example: TRK oncogene encodes a fusion protein that encodes a hyperactivated tyrosine kinase.

  • Associated cancers: Thyroid, Colon. These rearrangements can lead to constitutive activation of the kinase.

• (e) Insertional mutagenesis: Retrovirus-induced - viral DNA inserted into a proto-oncogene, activating its expression.

  • Rare event but significant in understanding oncogenesis.

Tumour Suppressor Genes

• Tumour suppressor genes regulate the cell cycle, DNA repair, and cell death, preventing uncontrolled cell growth.

• Mutation in a tumour suppressor gene can disrupt its function, leading to loss of growth control.

• Loss of function mutation, where the gene product is inactivated or absent.

• Example: TP53 gene - half of all human cancers have p53 loss of function mutation, making it a critical target for cancer therapy.

• Most commonly mutated gene in human cancers.

p53 - Cell Guardian

• p53 responds to various cellular stresses:

  • Lack of nucleotides, UV radiation, ionizing radiation, oncogene signaling, hypoxia, blockage of transcription.

• p53 blocks the replication of damaged or mutated cells, preventing the propagation of genetic errors.

• It can trigger:

  • Cell cycle arrest, providing time for DNA repair.

  • DNA repair, fixing damaged DNA to restore normal function.

  • Block of angiogenesis, preventing the formation of new blood vessels that feed tumors.

  • Apoptosis, inducing programmed cell death to eliminate damaged cells.

  • Senescence, causing cells to enter a state of permanent growth arrest.

• If these processes are successful, the cell can return to proliferation. Otherwise, the cell undergoes