cancer Lecture 1

The Cancer Chapter: Understanding Cellular Dysregulation

Cancer is a critically important topic due to its widespread impact. It is not a single disease but a series of diseases caused by many different mutations.

I. Multicellular Cooperation and Communication

In multicellular organisms, cells operate within a cooperative community, constantly communicating and collaborating to coordinate their behavior. This coordination is essential for the organism's overall health and function.

A. Mechanisms of Cellular Communication

  • Cells send, receive, and interpret a large number of signals simultaneously.

  • Signals can come from nearby cells or distant cells.

B. Socially Responsible Cellular Behavior

Through this communication and interpretation of environmental and cellular inputs, cells behave in a "socially responsible manner." This means they:

  • Rest: Halt division when appropriate.

  • Divide: Proliferate when needed.

  • Differentiate: Specialize into specific cell types.

  • Die (Apoptosis): Undergo programmed cell death for the good of the organism.

Each cell's individual actions promote the health of the entire organism.

C. Consequences of Disturbed Harmony

Any disturbance that upsets this harmonious behavior can lead to trouble for the multicellular society. A cell acting selfishly puts the entire cooperative in jeopardy.

II. Signal Interpretation and Cell Fate

Cells receive a series of signals that dictate their actions:

  • Survival: A baseline set of signals tells a cell to simply survive and continue its current function.

  • Division: Additional signals (local or distant) can instruct a cell to divide.

  • Differentiation: A different combination of signals can prompt a cell to mature and differentiate into a specialized cell type.

  • Apoptosis (Cellular Suicide):

    • The absence of signals can itself be a cue for a cell to commit apoptosis.

    • Other cells (e.g., cytotoxic T cells in the immune system) can directly instruct a cell to undergo apoptosis.

It is crucial for cells to not only receive but also actively "listen" to and interpret these signals.

III. Defining Cancer: A Selfish Disease

Cancer: A disease in which an individual mutant clone of cells prospers at the expense of its neighbors and ultimately the entire multicellular cooperative.

  • The cancerous cell divides more frequently, consuming more nutrients and space than is beneficial for the surrounding cells and the organism.

IV. The Mechanism of Selfish Cellular Behavior

A cell becomes selfishly behaving due to suffering mutations.

A. Cancer Critical Genes

Mutations occur in what are referred to as cancer critical genes. These genes are related to:

  • Cell division (receiving cues to divide).

  • DNA damage repair.

Mutations in these genes promote selfish behavior by a single cell, jeopardizing the entire cooperative.

B. The "Not Listening" Analogy

A cancerous cell can be likened to a person wearing noise-canceling headphones, blocking out all information from its environment and other cells. It "doesn't care" about the signals telling it how to behave.

C. Bypassing External Signals

Mutated cells often bypass the need for external signals to divide:

  • Some mutations eliminate the requirement for signaling from other cells.

  • They can turn on signal transduction pathways "downstream" of the signaling molecule (ligand for a receptor) even in the absence of the actual signal.

  • This allows them to continue dividing even when environmental cues and signals from other cells are telling them to stop.

V. Consequences and Detection of Cancerous CellsA. Immune System's Role and Limitations

  • Normally, the immune system (e.g., cytotoxic T cells) can recognize and eliminate abnormal cells that look or behave unusually or present strange peptides on their MHC1.

  • However, if a cancerous cell does not appear outwardly abnormal, the immune system may fail to recognize it, allowing it to behave selfishly and grow unchecked within the cooperative.

B. Tumor Development Timeline

By the time a typical human tumor is detected, it has often been developing for many years and may contain a billion or more cells, indicating extensive uncontrolled cell division.

VI. Socially Responsible Cell Division

Cell division is a tightly controlled process that is essential and "socially responsible" under specific circumstances:

  • Wound Repair: To heal damaged tissues.

  • Fighting Infection: To expand populations of immune cells (e.g., B cells, T cells) with useful receptors.

  • Organism Growth: During development and growth phases.

  • Replacing Worn-Out Cells: To maintain tissue integrity and function (e.g., skin cells, blood cells).

In these cases, signals come to the cell, are bound, summed up, and if they align with one of these purposes, the cell may divide.

VII. Types of Stimulatory Signals for Cell Growth and Division

Two general terms for signals that stimulate cell growth and proliferation:

  • Mitogens:

    • Extracellular signals (from other cells).

    • Initiate or promote mitosis (cell division).

  • Mitogens:

    • Extracellular signals (from other cells).

    • Initiate or promote mitosis (cell division).

  • Growth Factors:

    • Second class of signaling molecules that promote cell division.

    • Function by increasing the cell mass (cell growth).

    • Importance: Ensures that when a cell divides, the daughter cells are the same size as the parent cell, preventing reduction in cell size/volume over generations. This requires the cell to increase its organelles and proteins before division.

    • Often work in combination with mitogens to prepare the cell for division (e.g., "put on weight," "double our weight," "get more organelles," "make more proteins").

VIII. Cell Cycle Control and Checkpoints

Cells do not divide without proper controls. The cell must monitor its progression through the cell cycle to ensure division is carried out accurately, at the appropriate time, and under suitable internal conditions.

Checkpoints: Places in the cell cycle where progression is halted unless specific criteria are met.

A. Major Checkpoints1. G1 Checkpoint (Start Checkpoint)

  • Location: Between G1 phase and S phase.

  • Criteria for Progression:

    • Mitogens Present: The cell has received external signals (from neighbors) indicating it's socially responsible to divide.

    • Adequate Cell Size: The cell is large enough to divide into two viable daughter cells.

    • Sufficient Nutrients: Enough resources in the environment to support cell activities and division.

    • Undamaged DNA: The cell's DNA is intact and free from damage.

  • Consequence of Failure:

    • Cell arrests at G1.

    • Initiates DNA repair mechanisms.

    • If damage cannot be repaired, the cell should commit cellular suicide (apoptosis) to prevent passing on damaged DNA.

    • Why it's crucial: Progressing with damaged DNA would lead to duplication of errors in S phase, resulting in two copies of damaged DNA in G2, which would be passed to daughter cells, solidifying a mutation.

2. G2 Checkpoint

  • Location: Between G2 phase and M phase (mitosis).

  • Criteria for Progression:

    • Adequate Cell Size: The cell has continued to grow and accumulate mass (proteins, organelles) during G2.

    • Successful Chromosomal Replication: All chromosomes have been accurately and completely replicated during S phase.

  • Consequence of Failure: Prevents partitioning incompletely replicated DNA into daughter cells.

3. Metaphase Checkpoint (Spindle Assembly Checkpoint)

  • Location: During metaphase of mitosis.

  • Criteria for Progression:

    • All Chromosomes Attached to Mitotic Spindle: Every sister chromatid must be correctly attached to spindle microtubules from opposite poles.

  • Consequence of Failure:

    • Cell arrests at metaphase, preventing progression to anaphase.

    • Why it's crucial: Failure to attach all chromosomes would lead to an uneven distribution of chromosomes during anaphase, resulting in daughter cells with an incorrect number of chromosomes (aneuploidy), which is a severe mutation.

B. Cellular Suicide (Apoptosis)

  • If a cell detects a problem at a checkpoint that it cannot fix, it should commit cellular suicide (apoptosis).

  • This prevents the propagation of errors or damaged cells, which could be dangerous for the multicellular organism.

IX. Tumor Formation and Cancer: Loss of Homeostasis

Cancer is fundamentally a loss of internal balance (homeostasis) in cell proliferation and death, where certain cells behave "selfishly" and do not coordinate with the cooperative multicellular organism.

A. Homeostasis in Cell Number

  • Our bodies maintain a relatively stable number of cells within a range.

  • This balance is achieved by regulating both cell division and cell death.

B. Mechanisms Leading to Excessive Cell Numbers (Tumors)

An excessive amount of cells (a tumor) can result from a disruption in the balance between cell division and cell death:

  1. Increased Cell Division Rate:

    • If the rate of cell division increases while the rate of cell death remains normal, there will be an overall increase in cell number.

  2. Decreased Cell Death (Apoptosis):

    • If the rate of cell death decreases while the rate of cell division remains normal, cells accumulate, leading to an increased number.

  3. Both Increased Cell Division and Decreased Apoptosis:

    • This is the condition characteristic of most cancers.

    • Cells divide at an accelerated rate AND actively avoid programmed cell death.

    • This dual mechanism leads to rapid and significant accumulation of cells, forming a tumor.

Cancer cells are often described as ignoring external signals and internal controls, failing to coordinate their behavior with the needs of the surrounding tissues and the organism as a whole.