REGULATION OF CELL DIVISION AND TUMOR GROWTH

(The results of the work [1] are briefly listed below)

V. T. Vertushkoff

Dniepropetrovsk, 49128, Ukraine

www.vertushkov.dp.ua.

Date of place: 10.04.2000

State of oppression of cell growth caused by the influence of superfluous (over-optimal) concentrations of growth factors is considered as a stimulation of cell division or starting mechanism of a program, aimed at the cells passing through mitosis. In the normal tissue a process of active growth inhibition is developed under the influence of the inner-cell mechanisms in each cell individually, in the course of cell evolution. Cell division stimulus is constantly effecting malignant tumor cells during all the mitotic cycle. This stimulus prevents from their quitting of the cycle and subsequent differentiation, and determines the main feature of these cells, namely, unlimited reproduction.

It is known, that a malignant tumor cell doesn’t possess any qualitatively new metabolic ways, not inherent to the normal tissue cells. Only quantitative changes of some metabolic parameters are observed (for instance, glycolysis), Thus, the superfluous concentrations of growth factors are typical for tumor cells in their micro-environment. It is supposed that:

1)     Under reaching of some critical parameters, in the normally growing cell the process of active growth inhibition caused by superfluous (over-optimal) concentrations of growth factors influencing the cell, is developed.

2)     State of cell growth oppression is regarded as a stimulus of cell division or as mitosis starting mechanism.

An optimal (the most rapid) growth of cells and minimal duration of mitotic (cell) cycle corresponds to the optimal concentration of growth factors in the inter-cell environment of normal growing tissue. Processes taking place in cells are principally distinguished depending on lower or higher level of growth substances’ optimal concentrations. Growth factors’ concentrations within the limits not exceeding the optimal ones provide both growing and division of cells and differentiation of newly created elements, according to their functions [2] The over-optimal doses of growth factors act as the natural stimulus of cell division, but not as a cell growth regulator. Injection of large quantities of estrogens to the animals accelerates in target tissues the mitosis of cells, ready for division, and reduces mitosis duration. In the cells not ready for division, the superfluous concentrations of hormones evoke deep metabolic reconstruction, because of which cell growth slowing-down occurred (block G1—S) [3]. This data directly points out that growth factors in concentrations oppressing cell growth act as a stimulus of cell division. Inhibition of growth in cells ready for division activates the chain of inter-cell processes well coordinated in space and time, which in the aggregate make mitotic cell division. Superfluous concentration of growth factors is created in each cell of normal growing tissue individually, as it becomes ready for division. It corresponds to the point of view, in accordance to which the cells concur for consumption of hypothetical substance which threshold concentration is required for cell transition to its division [4]. Normal cell division, probably, is preceded by the period of growth termination [5].

Thus, the influence of superfluous growth-stimulating doses on cells can be considered the natural biological act, on condition that these substances affect cells ready for division. However, the over-optimal concentrations of growth factors are constantly influencing the tumor cells during all the mitotic cycle This act is evidently unnatural and is not inherent to the normal tissue cells. Jaffe et al. [6] studied the relationship between concentrations of PGE and rates of cell proliferation in vitro under basal conditions as well as under conditions of stimulation and inhibition of PGE synthesis. In four cell lines (a monolayer derivative of human adenocarcinoma), an inverse relationship was documented under all conditions examined. As it is demonstrated in Table 1, during control cultures slowly growing cells synthesized significantly more PGE and this correlated very well with an apparently increased enzymatic ability to convert known quantities of arachidonic acid to PGE. Addition exogenous PGE1 to culture medium (1 μg/ml) resulted in a mean 41% inhibition of cell proliferation. Stimulation of endogenous PGE synthesis using dibutyryl cyclic AMP (mean increase 54%) resulted in a similar degree of inhibition of cell replication. On the other hand, 61% inhibition of PGE synthesis by including indometacin in the media 10-8 M) resulted in a mean 23% stimulation of cell replication, and the stimulatory effect of indometacin was reversed by the addition of PGE1 to the final concentration of 10 ng/ml.

TABLE 1. Relationship between PGE production and rates of cell proliferation in vitro [6].

 

Cell line

 

Mean doubling time (hours)

 

Daily PGE production (ng/106 cells/day)+

 

PGE synthetic ability* (ng/mg protein)

 

HT-29

11.5

0,13

 

HEp-2

23,0

0,69

22,6

L

30,0

0,98

42,3

HeLa

37,5

5,74

244,0

 

+ Mean total (medium + cells) daily synthesis during log phase growth.

* The synthetic ability of tumor cell homogenates to convert added arachidonic acid to PGE2.

As it is known, PGE act as inter-cell mediators of tropal hormones. Data listed below indicates that PGE content in the cultural environment exceeds the optimal level considerably. If PGE concentration was equal to the optimal or lower, the further lowering would be accompanied by decrease in the proliferation activity, instead of increasing (by 23%), as it actually occurs.

If a hypothesis of superfluous concentration of growth factors as a cell reproduction stimulus is true, the duration of cell cycle in malignant tumors should be longer, than minimal in homologous normal tissues from which tumors developed. It is proved by investigations. As Table 2 shows, under malignancy of rapidly proliferating tissue of mouse thymus gland, cell cycle duration becomes longer. This cycle is cut down in liver and other slowly proliferating tissues after malignancy, but (and it is essential) it doesn’t reach the values typical for the intensive growth of corresponding normal tissues. “In all the cases, when cell cycle duration in normal tissues was longer than minimal one (all the tissues, except for lymphatic), considerable reduction of this value occurred after malignancy. Such conclusion is reasonable under comparison of tumor and non-stimulated tissues of the adult organism. In the same normal tissues under stimulation (hormones, co-carcinogens, regeneration) cell cycle is shorter than in tumors” [7]. Based on this data, the relationship between the character of tissue growing in mouse organism and concentration of growth factors is presented in Figure 1.

 

TABLE 2. Comparison of cell cycle in normal tissues and primary tumors [7]

OBJECT

Time, hours

Ñ

G1

S

G2

Mouse thymus gland

 

 

 

 

Big lymphocytes, norm

6,8

0

5,5

1,3

The same, lymphoma

7,6

0

6

1,6

Medium lymphocytes, norm

8,2

1,4

5,5

1,3

The same, lymphoma

20,2

12

6

2,2

All the cells, norm

12

3

7

2

The same, lymphoma

15

4,8

8

2,2

Mouse pregastris

 

 

 

 

Norm

55

45

7

3

Hyperplasia

24

16,4

6,6

2

Papillomas

18

11,4

4,6

2

Cancer (2nd generation)

8-12

2-6

3,6

2,2-2,5

Mouse back skin

 

 

 

 

Norm

80

66

8

6

Tvin-60 stimulation

10

3

4,4

2,6

Cancer

32

–

8

–

Hamster cheek epithelium

 

 

 

 

Norm

130

–

8,6

–

Cancer

11-14

2-5

6-8

2

Mouse lactiferous gland

 

 

 

 

Norm

64

37,7

21,7

4,6

Hormonal stimulation

13

1,3

9,2

1,5

Adenocarcinomas

35

21-24

10

1-4

Rat liver

 

 

 

 

Norm

47,5

28

16

1,7-1,8

Regeneration

15

3,5

8

3,5

Hepatomas (tetraploid)

31

12

17

2

 

Concentration of growth factors, arbitrary units

Fig.l. Assumed relationship between tissue growth character and growth factors’ concentration in mouse organism

1 – back skin; 2 – lactiferous gland; 3 – pregastris;

4 – medium lymphocytes of thymus gland.

Cell cycle duration data are taken from Table 2.

 

The reaction of normal cells to the increase of growth factors dose is not invariable. Quantitative changes transforms into qualitative ones under reaching of the over-optimal concentrations. Prepared cells react to superfluous doses of growth factors as to cell division stimulus, that is they start mitotic division. The reaction of unprepared cells has a distort character. Persistent continuous stimulation of cell division at stages when cells are not ready for division yet, finally leads to the appearance of signs array characterizing a cancer cell. An existence of optimal concentration of growth factors and minimal duration of mitotic cycle testify that there is a critical proportion between respiration and glycolysis in a cell. Under cancer the glycolysis increase is accompanied, apparently, by respiration efficiency reduction. Prostaglandins, which there are intracellular mediators of growth of the hormones, are able to disengage an oxidizing phosphorylation, that is considered as the main link in the mechanism of their influence on the cell.

 

References

[1] Vertushkoff V.Ò. 1980. Modern Biology Achievements (Óñïåõè ñîâðåìåííîé áèîëîãèè), 90, 3 (6), 436

[2] Kholodny N.G. 1939. Phytohormones, Kiev, UkrSSR Academy of Science Edition.

[3] Yepifanova O.I. 1965. Hormones and Cell Reproduction. M., “Nauka”.

[4] Hall E.J., Lajthal L.G., Oliver R. 1962. Brit. Radiol., 35,414,388

[5] Hamburger Ê. 1975. Compt. rend. trav. Lab. Carlsberg, Ser. physiol., 40, 15,175.

[6] Jaffe Â.M. 1974. Prostaglandins, 6, 6, 453.

[7] Frankfurt 0.S. 1975. Cell Cycle in Tumors. M., “Medicina”.

E-mail: vertushkov@ua.fm

V. Vertushkoff,

Kommunarovskaya Str., 16

Flat 332,

city of Dniepropetrovsk,

UKRAINE, 49128