Mitosis is the process by which a single cell divides into two identical daughter cells. This fundamental biological process enables growth and tissue repair by ensuring the precise duplication and distribution of genetic material. Cancer is characterized by uncontrolled cell proliferation and a failure to adhere to the body’s regulatory signals. Studying the mechanics of normal mitosis has been foundational for understanding how cancer cells bypass growth controls, providing insights into the disease’s origins and treatments.
Understanding Normal Cell Division
The life of a cell is governed by the cell cycle, a tightly regulated sequence of events divided into interphase and the mitotic (M) phase. Interphase is the preparatory period, consisting of the G1 phase for cell growth, the S phase where DNA synthesis occurs, and the G2 phase for final preparations before division. The M phase is the culmination of this preparation, where the cell physically divides its nucleus and cytoplasm.
Mitosis itself is a continuous process conventionally described in four stages, each requiring remarkable precision. During prophase, the replicated genetic material condenses into visible chromosomes, and the mitotic spindle begins to form. In metaphase, the chromosomes align perfectly along the cell’s equatorial plate, ensuring that each daughter cell receives a full set.
Anaphase is characterized by the synchronous separation of sister chromatids, which are pulled toward opposite poles by the shortening spindle fibers. Finally, telophase reverses prophase, with the nuclear envelopes re-forming around the two separate chromosome sets. This process, which produces two genetically identical daughter cells through cytokinesis, establishes the baseline of cellular behavior that malignant cells must corrupt to survive.
Identifying the Cell Cycle Regulators
The transition between phases is overseen by cell cycle checkpoints. These checkpoints halt progression if specific conditions, such as DNA integrity or proper chromosome alignment, have not been met. Knowledge of these regulatory points was a major leap in understanding cancer causation.
Cell cycle progression is driven by cyclin-dependent kinases (CDKs), whose activity depends on their association with activating proteins called cyclins. Cyclins are synthesized and degraded rhythmically, creating “waves” of CDK activity that push the cell from one phase to the next. For instance, Cyclin B and CDK1 activity are high during the transition into and throughout mitosis.
Cancer cells often harbor mutations in the genes that encode these regulators. Tumor suppressor proteins like p53 and Retinoblastoma protein (Rb) are important at the G1 checkpoint, which controls entry into the DNA synthesis phase. Wild-type p53 responds to DNA damage by inducing cell cycle arrest, allowing time for DNA repair or initiating programmed cell death if the damage is too severe.
The Rb protein normally binds to transcription factors, blocking the expression of genes required for cell division. This inhibitory action is released when CDKs phosphorylate Rb. Loss of functional p53, which is altered in about half of human cancers, or a non-functional Rb pathway allows damaged cells to proceed unchecked into replication.
Linking Faulty Mitosis to Genomic Instability
A failure in mitosis has severe consequences for daughter cells, leading to genomic instability. This instability, defined as an increased rate of accumulating genetic alterations, is a hallmark of nearly all aggressive tumors. The most common structural outcome of mitotic failure is aneuploidy, the presence of an abnormal number of chromosomes.
Errors in the spindle assembly checkpoint (SAC) are a primary cause of this instability. If the SAC is compromised, the cell may prematurely enter anaphase before all chromosomes are correctly aligned and attached to the spindle. This results in chromosome missegregation, where daughter cells receive an unequal number of chromosomes.
The presence of supernumerary centrosomes is another common defect observed in cancer cells that disrupts the mitotic process. Too many centrosomes can lead to the formation of multipolar spindles, resulting in cell division into three or more cells with unequal and unstable genomes. This chromosomal chaos fuels tumor heterogeneity and drives the evolutionary capacity of cancer cells, often leading to drug resistance.
Developing Targeted Cancer Therapies
The study of the mitotic machinery has translated into clinical strategies for diagnosis and treatment. One application is the use of proliferation markers, like Ki-67, to gauge tumor aggressiveness. Ki-67 is present during all active phases of the cell cycle (G1, S, G2, and M) but absent in resting cells, indicating the fraction of cells actively dividing within a tumor.
Many effective chemotherapy drugs exploit the vulnerability of the mitotic apparatus. These microtubule-targeting drugs interfere with the formation and function of the mitotic spindle. Taxanes, such as Paclitaxel, act as microtubule-stabilizing agents, preventing the spindle from breaking down and arresting the cell in metaphase.
Vinca alkaloids, like Vinblastine, are microtubule-destabilizing agents that prevent tubulin polymerization. Both classes of drugs ultimately trigger programmed cell death by activating the SAC. This strategy selectively targets rapidly dividing cancer cells, although it also causes side effects in normal, fast-dividing cells like those in the bone marrow and hair follicles.