**3. Cell regulatory mechanisms: The cell cycle**

Carcinogenesis, or the sequence of events leading to cancer, is a multistep process involving both intrinsic and extrinsic factors. In the normal tissue, there are numerous regulatory signals that instruct cells when to replicate and when to die. In a cancer cell these regulatory mechanisms become disabled and the cell is allowed to grow and replicate unchecked. Thus at the most fundamental level cancer is caused by abnormal gene expression. This abnormal gene expression occurs through a number of mechanisms including direct damage to the DNA, and inappropriate transcription and translation of cellular genes. Carcinogenesis has been demonstrated abundantly to be induced or at least caused by exposure to certain types of chemicals (carcinogens). The mechanisms are elaborated on subsequently. The cell cycle plays an important role in this regard. It is concerned with the processes that govern the life and death of cells and through transient delay in G0 phase or outright apoptosis (programmed cell death) might be able to prevent damage in the DNA of a cell that may proceed to carcinogenesis. In the normal cell, replication of the DNA and cell division is stimulated by the presence of growth factors that bind receptors at the cytoplasmic membrane and initiate a cascade of intracellular signals. Once these signals reach the nucleus they induce transcription of a complex array of genes producing proteins that mediate progression of the cell cycle culminating in mitosis or cell division. One remarkable contribution of biomedical engineering is the introduction of flow cytometer equipment which enable stages of the cell cycle to be followed and disorders or disruptions there of detected.

The cell cycle is conventionally divided into four (4) phases, although there is the subsidiary G0 phase. The duration of each of these phases varies depending on factors such as cell type and localized conditions within a given tissue (microenvironment). At the end of mitosis (M) daughter cells enter gap 1 (G1) phase.

Fig. 2. Schematic representation of Cell Cycle.

If conditions are favourable cells enter the synthetic (S) phase of the cycle where the entire genome is replicated during DNA synthesis. Following 'S' phase, cells enter the gap 2 (G2) phase before proceeding through mitosis again. A critical phase boundary exists early in the G1 phase called the restriction point. This is the point at which the cell must decide to either enter the cell cycle once more or to secondly move into a state of quiescence; G0 phase. Once committed to this pathway, the cell can either remain in this state of replicative quiescence until it receives a signal to divide again. Alternatively the cell can proceed down a path that leads either to terminal differentiation or to apoptosis. Movement of a cell through the cell cycle is regulated by an enormously complex array of proteins.

The proteins include:

74 Biomedical Science, Engineering and Technology

carcinogenesis. In the normal cell, replication of the DNA and cell division is stimulated by the presence of growth factors that bind receptors at the cytoplasmic membrane and initiate a cascade of intracellular signals. Once these signals reach the nucleus they induce transcription of a complex array of genes producing proteins that mediate progression of the cell cycle culminating in mitosis or cell division. One remarkable contribution of biomedical engineering is the introduction of flow cytometer equipment which enable stages of the cell cycle to be

The cell cycle is conventionally divided into four (4) phases, although there is the subsidiary G0 phase. The duration of each of these phases varies depending on factors such as cell type and localized conditions within a given tissue (microenvironment). At the end of mitosis

followed and disorders or disruptions there of detected.

(M) daughter cells enter gap 1 (G1) phase.

Fig. 2. Schematic representation of Cell Cycle.


Binding of an appropriate growth factor at the cell surface starts a signaling cascade that ultimately leads to the expression of the G1 phase cyclins. It is important to remark that in normal cells, external stimuli (factors) such as growth factors are absolutely needed for the cell to proceed beyond the restriction point. Beyond this point, the cell is committed to DNA replication and cell division. Interference with the normal signal transduction pathway by chemical carcinogens, the mechanism notwithstanding can transform a cell into a state of proliferation that is not regulated by normal physiological controls (carcinogenesis). This basically is broadly the molecular basis of carcinogenesis.

### Table 2. Proteins Controlling the Cell Cycle.

It is note worthy that all phases of the cell cycle are regulated by the micronutrient zinc. Thus zinc deficiency common in many developing countries (WHO, 2002; Ames, 2010) can be risk factors in chemical carcinogenesis. Ho et al (2003) have elegantly demonstrated this in their studies. This is an area where biomedical engineering has contributed significant in the last five or more decades by the production of flame absorption spectrophotometers (FAAS) and later the graphite furnace (carbon rod) (GFAAS). This was followed by inductively coupled plasma mass spectrometer which allows for simultaneous multi element analysis. These equipment have exquisite sensitivities which enable the status of zinc and many other micronutrients to be detected and indirectly play a preventive role; reducing risk of cancer.
