In normal tissues, each cell either proliferates or commits suicide*2 as needed while maintaining harmony as an individual to perform required functions. For instance, the proliferation of epithelial cells are suppressed upon contact with the adjacent cells or the extracellular matrices*3. Otherwise, their unrestricted proliferation in the epithelium may possibly lead to an overflow of cells from the epithelial surface. In reality, however, the skin does not multiply so far as it becomes badly corrugated, nor does the mucosal epithelium of the trachea proliferate forever to obstruct the air passage. As mentioned above, cancer cells proliferate in an autonomous manner, i.e., arbitrarily irrespective of skin corrugation or trachea obstruction. One of the causes of this is the fact that the suppression of cell proliferation, which can be observed in normal tissues, is not functioning correctly.
Research on cancer cells has revealed a number of facts explaining cellular carcinogenesis. The molecular level elucidation of the process of cells developing into carcinoma to start autonomous proliferation has brought important information to light in understanding the behavior of normal cells including proliferation. Several concrete examples are given below.
*2 This is called apoptosis. See Column below
*3 Microenvironments formed by proteins and so forth adjacent to the cells.
In normal individual organisms, the emergence of abnormal cells prompts immunocompetent cells in charge of individual defense to induce the death of abnormal cells. This cell death occurs by an inherent mechanism of cells to kill themselves and is called apoptosis.
The initiation of apoptosis is relayed to cells through signal transduction (see Column at the bottom). Upon receiving the signal, the cells activate enzymes to decompose intracellular proteins, breaking up a series of proteins needed for their subsistence. Subcellular organelles such as nuclei are also destroyed, and the cells disappear after being absorbed in the form of multiple vesicles. Cancer cells, however, are able to proliferate infinitely without being affected by this apoptotic mechanism.
In addition to providing defense against cancer, apoptosis plays pivotal roles in ontogeny. For example, there is a period when human fetuses possess fin-like membranes between their fingers, which eventually disappear in the course of their growth in the womb. This is also due to apoptosis: nonessentials during the process of growth are preprogrammed to vanish. This explains the reason why apoptosis is also called programmed cell death. Apoptosis is known to occur in cells damaged by various causes as well, but in such cases, cues to initiate apoptosis come from changes in intracellular substances.
Abnormalities in Regulation of Cell Proliferation
Fig. 7-2. Carcinogenesis Process
Rb controls the cell cycle while changing its intracellular states. Abnormal Rb cannot suppress the progress of the cell cycle.
Retinoblastoma is a type of cancer primarily found among infants and is hereditary in nature. In many cases, examination of the cancer cells of this disorder has led to the detection of an abnormality in a specific gene. The protein produced by this gene was named Rb after retinoblastoma; Rb does not function in the cancer cells of retinoblastoma. Progress in research has gradually demonstrated an important role of Rb in the control of the cell cycle. Cell proliferation occurs through a process called the cell cycle (Fig. 7-2). Although cell proliferation proceeds with a single cell dividing into two, each cell cannot survive just by dividing into two in a random manner. Cells multiply by going through the following phases: the phase to prepare proteins etc. required for replication; the phase to replicate chromosomes in nuclei, the phase to apportion integral cellular parts equally including the chromosomes (the phase that can be observed visually using instruments such as a microscope), and the phase in which cells perform their functions in tissues (the phase in which they do not divide). Rb controls the progress of these phases suppressively. Without this suppression of the cell cycle, it is easily conceivable that cell division continues incessantly.
Abnormalities in Stimulation of Cell Proliferation
We have seen the examples of cellular carcinogenesis as a result of the occurrence of abnormalities in the suppression mechanism of cell proliferation. We will be next seeing the examples of cellular carcinogenesis as a result of the occurrence of abnormalities in the promotion mechanism of cell proliferation. Although it was originally discovered in a study separate from that of Rb, a protein called epidermal growth factor receptor (EGFR) *4, exemplifies other abnormalities in cancer cells (see Column at the bottom).
In cancer cells of lung cancer or some other types of cancer, abnormalities sometimes occur in EGFR, a protein which is expressed on the plasma membrane. Epidermal growth factor (EGF) is a substance capable of stimulating cell proliferation. By combining with EGFR expressed on the surface of the plasma membrane, it promotes proliferation of cells. Once the stimulus ebbs away, the promotion of cell proliferation via EGFR also ceases. Abnormal EGFR found in cancer cells persists in a state as if it was bound to EGF when in fact it is not, thus continuing to promote cell proliferation.
There is another important protein in relation to EGFR. The protein Ras is one of the first examples that clarified the relationship between cellular carcinogenesis and protein abnormalities. Ras exists in a pathway delivering information from EGFR and other numerous receptors in succession. It is involved in a number of processes of cell proliferation including the one by EGF, as well as the control of the cell cycle associated with Rb. Abnormal Ras is therefore observed in diverse cancer cells.
Each of the examples shown here in connection with protein abnormalities and cellular cancer ratio is undoubtedly a crucial factor. Nevertheless, the occurrence of a single abnormality in these proteins alone will not render cells cancerous; it simply induces apoptosis. Normal cells receive stimuli required for the initiation of proliferation extracellularly and transmit them to intracellular systems promoting the cell cycle. A variety of signal transduction pathways ingeniously regulate one another, thereby letting cells proliferate as needed and inhibiting growth as appropriate. In preparation for the failure of such systems, cells are provided with the mechanism to induce their own death as a safety net. The malfunctioning of the safety net on account of accumulation of several abnormalities including ones not exemplified here triggers disorderly cell proliferation. Cellular carcinogenesis therefore requires a multitude of steps.
It has been a while since we started hearing people discuss the relationship between tobacco and cancer. Epidemiologically, tobacco is known to increase the risks of not only lung cancer but also stomach cancer, breast cancer, and bladder cancer. It contains no fewer than 60 types of experimentally confirmed chemical substances regarded as carcinogens, at least 15 of which are substantiated to be carcinogenic for humans.
The addictive nature of tobacco is attributable to nicotine, whose metabolism depends on the same enzyme responsible for the metabolism of NNK*5, one of the carcinogens contained in tobacco (activation as a carcinogen). The activity of this enzyme varies among individuals. An observation suggests that in response to a decrease in nicotine in the body because of its insufficient content in a cigarette, increased excretion in their urine, or increased metabolism, nicotine-dependent smokers try to supplement the deficiency of nicotine by augmenting the amount of tobacco they smoke. Consequently, the stronger the activity of this nicotine-metabolizing enzyme is, the more tobacco they smoke. Conversely, stronger activity of this enzyme signifies a higher risk of contracting cancer as more NNK is metabolized to be carcinogenic. To make matters worse, on top of the rampant metabolism of NNK, smokers start smoking more owing to the abovementioned reasons, thus resulting in a further increased risk of carcinogenesis. This is almost as if tobacco was predestined to cause an epidemic of cancer among human groups.
*4 In the molecular level, stimuli are transmitted to cells when receptor proteins bind certain substances. These substances are generally referred to as signal molecules, hormones being one of them. Information transmission resulting from the combination between signal molecules and receptors is called signal transduction. Signals are transmitted via other small molecules even within cells, eventually giving rise to changes in the behavior of cells such as the expression of new proteins. See Column at the bottom
Cell Signal Transduction
Stimuli and information on surrounding environments are transmitted to cells through a mechanism called signal transduction. Substances mediating signal transduction are commonly referred to as signal molecules, which bind to protein receptors on the surface of cells to transmit signals to them. Combinations between receptors and signal molecules are fixed to a certain extent, and this is crucial in delivering appropriate signals to appropriate cells. Signals transmitted to receptors elicit activation of intracellular substances as well as movement of substances inside and outside cells, thereby prompting subsequent changes and eventually altering cellular functions.
We will discuss the signal transduction mediated by epidermal growth factor (EGF) in detail. EGF is secreted from various tissues and promotes cell proliferation. The binding of EGF to two EGFRs alters their chemical property. Another protein binds to the altered EGFR, and a signal is transmitted to the protein. The protein then delivers the signal to another protein named Ras, which is involved in a variety of signal transduction pathways. The signal is successively relayed down to other proteins. Finally, a signal protein enters a nucleus to induce gene transcription, thereby commencing the steps of protein synthesis (Column Fig. 7-2).
Column Fig. 7-2. An Example of Intracellular Signal Transduction
Receptors bound with EGF are altered in their chemical nature. Mediated by adaptor proteins working as a platform for signal transduction, signals are transmitted in succession. Transmission of signals causes changes in the chemical nature and local distribution of the proteins in the pathway.
Sugar tastes sweet to us as a result of signal transduction which starts with sugar working as a signal molecule transmitting signals to taste cells on the tongue. The sky looks blue to us primarily because light plays a role similar to signal molecules to initiate signal transduction in retinal cells. A vast array of biological reactions utilizes the mechanism of signal transduction. It can therefore be said that elucidating the process of signal transduction takes up a substantial part of understanding of the mechanism of living organisms.
Many medicines employed in medical treatment also make use of the mechanism of signal transduction. There are a wide variety of medicines such as one which binds to receptors by mimicking a certain signal molecule and one which interrupts signals by blocking receptors to prevent signal molecules from binding. Previously, it was often the case that the process of elucidating the working mechanism of already-discovered drugs led to the revelation of new signal transduction pathways. Nowadays, however, attempts are frequently being made to target a specific signal transduction pathway with a focus on developing a new drug which acts on the pathway for a desired effect (see Column in Section 4 Chapter 7).