Unit 5: Cell Adhesion, Extracellular Matrix, and Cancer

Cell Adhesion Molecules (CAMs)

CAMs are proteins located on the cell surface that are involved in binding with other cells or with the extracellular matrix (ECM). They are essential for holding tissues together and for cell communication.

Cadherins

• Function: Mediate cell-cell adhesion.
• Mechanism: They are calcium-dependent (their name comes from "calcium-dependent adherin").
• Binding: They typically mediate homophilic binding, meaning a cadherin molecule on one cell binds to an identical cadherin molecule on an adjacent cell.
• Role: Crucial for forming adherens junctions, which link the actin cytoskeletons of adjacent cells, providing strong adhesion in tissues (e.g., epithelial tissue).

Integrins

• Function: Mediate cell-matrix adhesion (attaching the cell to the ECM). They can also mediate cell-cell adhesion.
• Mechanism: They are transmembrane receptors.
• Binding: They mediate heterophilic binding, binding to proteins in the ECM such as fibronectin and laminin.
• Role: They link the ECM outside the cell to the actin cytoskeleton inside the cell, acting as signaling molecules that inform the cell about its environment.

Extracellular Matrix (ECM)

The ECM is a complex network of proteins and polysaccharides secreted by cells into the surrounding space. It provides structural and biochemical support to tissues.

Major Components of the ECM (in animals):

1. Collagens:
   • The most abundant protein in the human body.
   • Forms long, fibrous structures that provide tensile strength (resistance to stretching).
2. Elastin:
   • A protein that allows tissues to stretch and recoil (provides elasticity). Abundant in skin, lungs, and blood vessels.
3. Proteoglycans:
   • Core proteins with long chains of carbohydrates (glycosaminoglycans or GAGs) attached.
   • They are highly hydrated and form a gel-like "ground substance" that resists compression.
4. Adhesive Glycoproteins (e.g., Fibronectin, Laminin):
   • "Glue" proteins that help link cells to the ECM.
   • Fibronectin: Binds to collagen and integrins.
   • Laminin: A major component of the basal lamina (a specialized ECM layer).

Cancer: An Introduction

Definition: Cancer

Cancer is a collection of related diseases characterized by the uncontrolled division of abnormal cells. These cells have the ability to invade adjacent tissues and spread to distant organs (a process called metastasis).

This loss of control is due to genetic mutations that disrupt the normal regulation of the cell cycle and cell death.

Carcinogenesis and Promoting Agents

Carcinogenesis is the multi-step process by which a normal cell transforms into a cancer cell. It involves the accumulation of multiple mutations over time.

Agents Promoting Carcinogenesis (Carcinogens):

Carcinogens are agents that can cause mutations in DNA, leading to cancer.

• 1. Chemical Carcinogens:
  • Examples: Components of tobacco smoke (e.g., benzopyrene), asbestos, aflatoxin (from mold on peanuts), food preservatives (nitrites).
• 2. Physical Carcinogens:
  • Examples:
  • UV Radiation: From sunlight (causes skin cancer).
  • Ionizing Radiation: X-rays, gamma rays (can cause leukemia, thyroid cancer).

3. Biological Carcinogens (Oncogenic Viruses):

• Examples:
• Human Papillomavirus (HPV): Causes cervical cancer.
• Hepatitis B and C Viruses (HBV, HCV): Cause liver cancer.
• Epstein-Barr Virus (EBV): Causes Burkitt's lymphoma.

Oncogenes and Tumor Suppressor Genes

Cancer is fundamentally a disease of genes. Two main classes of genes are involved:

1. Proto-oncogenes and Oncogenes

• Proto-oncogenes: Normal genes that code for proteins that stimulate cell growth and division (e.g., growth factors, receptors).
• Oncogenes: Mutated, overactive versions of proto-oncogenes. A mutation in just one copy (allele) is enough to cause problems (it's a dominant mutation).
• Examples: ras (involved in signal transduction), myc (a transcription factor).

2. Tumor Suppressor Genes

• Function: Normal genes that code for proteins that inhibit cell division or promote apoptosis (cell death). They are the "brakes."
• Mutation: Cancer occurs when these genes are inactivated. Mutations must occur in both copies (alleles) to fail (it's a recessive mutation).
• Examples:
  • p53 ("Guardian of the Genome"): Detects DNA damage and can halt the cell cycle (at G1) or trigger apoptosis. It is mutated in over 50% of human cancers.
  • Rb (Retinoblastoma): A key inhibitor of the G1 checkpoint.

Characteristics and Molecular Basis of Cancer

Cancer cells exhibit a set of common traits, often called the "Hallmarks of Cancer" (popularized by Hanahan and Weinberg).

1. Sustaining Proliferative Signaling: They no longer need external growth signals (e.g., they have an active oncogene).
2. Evading Growth Suppressors: They ignore "stop" signals (e.g., they have mutated tumor suppressors like p53).
3. Resisting Cell Death: They evade apoptosis.
4. Enabling Replicative Immortality: Normal cells senesce (stop dividing) due to telomere shortening. Cancer cells often activate the enzyme telomerase to maintain telomere length and divide indefinitely.
5. Inducing Angiogenesis: They stimulate the growth of new blood vessels to supply themselves with nutrients and oxygen.
6. Activating Invasion and Metastasis: They lose their adhesion (e.g., loss of cadherins), break through the ECM, and spread to other parts of the body via the blood or lymph systems.

Treatment and Prevention of Cancer

Treatment Strategies

• 1. Surgery:
  • Physical removal of the primary tumor. Most effective for solid, localized tumors.
• 2. Radiation Therapy:
  • Uses high-energy radiation (X-rays, gamma rays) to damage the DNA of cancer cells, leading to their death.
• 3. Chemotherapy:
  • Uses cytotoxic drugs that target and kill rapidly dividing cells. This is why it also affects normal, rapidly dividing cells like hair follicles, gut lining, and bone marrow, causing side effects.
• 4. Targeted Therapy:
  • Newer drugs designed to attack specific molecular targets (e.g., an overactive oncogene protein) that are unique to the cancer cells. Often has fewer side effects.
• 5. Immunotherapy:
  • Boosts the patient's own immune system to recognize and attack cancer cells (e.g., checkpoint inhibitors).

Prevention Strategies

• Lifestyle Choices:
  • No smoking: The single most effective prevention strategy.
  • Healthy Diet: High in fruits and vegetables, low in processed meats.
  • Sun Protection: Using sunscreen to prevent UV-induced skin cancer.
  • Limiting Alcohol: Reducing alcohol consumption.
• Vaccinations:
  • HPV Vaccine: Protects against the primary cause of cervical cancer.
  • Hepatitis B Vaccine: Protects against a primary cause of liver cancer.
• Regular Screening:
  • Detecting cancer early (e.g., mammograms, colonoscopies, Pap smears) when it is most treatable.