The general problem of regulation of cell division and malignant transformation – II. An approach towards unraveling of the underlying mechanisms

| March 22, 2015 | 0 Comments

P M BHARGAVA

Published in: Current Science, 1983, 52, 234-239.

Abstract:

In the first part of this two-article series1 I have pointed out four basic questions that relate to the mechanism of regulation of cell division and malignant transformation. These questions are:

(I) What is the switch-chemically, biochemically, morphologically and functionally defined-that is put on when a resting cell is triggered by a mitogenic agent/ event into the division cycle?

(2) What is the language of the programme of the division cycle?

(3) What is the nature of the link between the switch and the programme?

(4) How does the switch get jammed in malignant transformation?

I have also pointed out that the above questions ‘comprise two non-overlapping subsets: the first consisting of questions I, 3 and 4, and the other of question 2. In this concluding part of the discussion, I will confine my attention only to questions I, 3 and 4. In regard to question 2, I would only state that virtually nothing is known today about the language of the programme of the division cycle- that is, the mechanism responsible for the occurrence, in a highly programmed manner, of the large number of events that occur during the cell cycle, which culminate in the formation of two cells starting from one.

The method that I wish to follow is construction of a model-essentially a hypothesis which attempts to provide tenable answers to the three questions and which makes unique, testable predictions. As the first step in the construction of models designed to provide explanation of natural events, is to look for clues which would constitute the basic premises of the model, some 15 years ago we set out to look for such clues in the plethora of information available in the area. It seemed that the following six observations might provide us the necessary clues.

(a) All cell types which can turn malignant, that is, which can exist in the normal and the malignant state, are, without exception, capable of existing in the resting and the dividing states. Further-and this is even more important-all cell types, without a single exception, that can exist in the dividing state and the true resting state that would satisfy the criteria already mentioned, are auxotrophic for a certain number of carbon-containing nutrients. Thus, mammalian cells require, for maintenance and growth, a certain number of amino acids, termed the essential amino acids, vitamins and unsaturated fatty acids (called the essential fatty acids). It is a point to ponder that animal cells-including human cells-need to have these ‘essential nutrients’ given to them in a preformed state as the cells arc either not capable of making these nutrients at all or make them at extremely slow rates that would not take care of the cells’ requirements. On the other hand, a lowly creature such as E. coli, can make all its carbon-containing compounds from a single carbon source, that is, glucose. Why has this discrepancy come about during the course of evolution? It does not seem unreasonable to argue that auxotrophy (requirement for certain preformed, carbon-containing nutrients, besides a primary carbon source such as glucose), while being a distinct disadvantage might have conferred upon the organism also an advantage that could have simply balanced off the disadvantage from the point of view of natural selection. Indeed, the course of human history might have been different if human beings possessed the ability to convert cellulose into glucose and to use glucose as the source of all carbon-containing compounds that the human organism needs for growth and maintenance! It may, therefore, be worthwhile to consider the possibility that the evolution of auxotrophy in higher organisms may be casually related to the evolution of the ability of the cell to exist in the resting and the dividing state, that is, to the mechanism that regulates growth-such regulation being clearly an advantage, as without such a regulation it simply wouldn’t have been possible for higher organisms such as a human-being, to perform many of their important functions. Similarly, it is possible that the ability to be transformed malignantly that is found in cells of higher organisms, may merely be an inevitable consequence of the ability of the cells to exist in the resting and the dividing state, and that the disadvantage that has accrued as a result of the evolution of the ability of a cell to be transformed malignantly, might have been more than amply compensated by the ability of the cell to exist in the resting and the dividing states, in the case of higher organisms.

(b) The transport of the essential nutrients (that is, those nutrients for which the cell is auxotrophic), is essential for the maintenance of both the resting and the dividing states.

(c) The rates of uptake or transport (the two terms being used here synonymously, although there is a subtle difference between them) of essential nutrients in cells that are dividing, that is, going from one cell cycle to another without going through an intermediate resting state, are about an order of magnitude greater than the rates of uptake of the same nutrients obtained in the resting or the Go cell2-6

(d) The increase in the rate of uptake of essential nutrients is an early event when a resting cell is triggered by a mitogenic agent or event into the division cycle. (It should, perhaps, have been mentioned earlier that when we talk of mitogenic events such as partial hepatectomy, it is most likely that the event leads to the generation of a mitogenic agent in the system.) In fact, no matter how early one looks, within the limitation of the techniques available, one finds that when a resting cell enters the division cycle, there is an increase in the rates of essential of nutrients. No exceptions ‘are known to this ‘rule’.

(e) When a resting cell is triggered into the division cycle, the primary event appears to occur on the cell surface. It is thus possible to make a resting cell enter the division cycle by mitogenic agents which are bound to solid substrates, under conditions that they cannot enter the cell (or the amount that enters the cell as a. result of cleavage from the solid substrate, is so small that, all by itself, it is unlikely to be able to initiate cell division).

(f) When a normal cell is transformed into a malignant cell, changes in the properties of the cell surface precede and are obligatory to the expression of the malignant phenotype, that is, the general characteristics of malignant cells.

HOW TO CITE

The general problem of regulation of cell division and malignant transformation – II. An approach towards unraveling of the underlying mechanisms. P M BHARGAVA, Current Science, 1983, 52, 234-239.

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