Medical Hypotheses U&ypaiur(1992) OLqmmOmnpUKLtd19Q2

39.7344

Discontinuity in the Competitive Interaction of Tumor Cells with the Tumor-Bearing Host-a Hypotheses Z. DOUVLIS Lands&

62, W-2856

Sandstedt- Wurthfleth,

Germany

Abstract-The hypothesis put forward here is that during the growth of a primary tumor ending in metastasis formation, phases occur in which ‘unfavourable’ conditions arise for the tumor cells. It is proposed that, in order to overcome these ‘unfavourable’ situations, the tumor cells subsequently secrete a substance designed to have a ‘dysfunctional’ effect on the normal ceils. On the assumption of such a discontinuous secretion by the tumor cells, an investigation is made into the behaviour of certain tumors in humans, together with the findings of previously conducted tests. This leads to the formulation of possible concepts for prophylaxis and treatment. In conclusion, an attempt is made to locate what would be the precise target of such a hypothetical substance.

Hypothesis

tumor cells is the reason for its secretion, or rather a consequence of it. In view of the tumor cells’ natural ‘interest to survive’, the destruction of the tumorbearing host would appear to be merely the unintended result. Subsequently, it must be presumed that by secreting such a substance (in the following symbolized with Ax) the tumor cells are trying to overcome an ‘unfavourable’ situation which cannot be overcome by other known substances, e.g. structure-dissolving ferments, namely collagenase, proteinase and hyaluronidase (4 1). What, though, would constitute an ‘unfavourable’ situation for tumor cells?

If the same quantity of tissue, corresponding to a primary tumor and its metastases in its terminal stage (taking into account all circumstances of localization) in a syngeneic tumor-bearing host, were to be excised from a healthy host, it is quite possible that this would not equate to the final stage. This gives rise to the hypothesis that the tumor cells exert a ‘dysfunctional’ influence, which gradually goes on to embrace the whole organism beyond the tissue directly enclosing the tumor and finally destroys it. This influence would have to be attributable to a substance being produced and secreted by the tumor cells, perhaps comparable to so-called toxohormones (26, 41). The question now arises as to whether the destruction of the host by the substance produced by the Date received 20 December 199 1 Date accepted 2 April 1992

a.

73

Do the normal cells enclosing the tumor present an obstacle to its growth as result of their normal function? And if so, in what way?

74 b.

MEDICAL HYFornEsEs If it is true that the substance Ax is meant to have an effect on the normal cells, what then would be its effect on tumor cells? The following is an attempt to provide answers to

these questions. Unfavourable situations for tumor cells and discontinuous Ax-secretioHccording to the hypothesis

Tumor cells forming in a tissue area which is enclosed by normal cells must protect their nutritional supply in order to survive. It follows that the quantity of nutrients originally intended for a particular number of cells now has to be shared among a larger number of cells. If one were now to assume that the ‘resistance’ of normal cells against the ‘withdrawal’ of nutrients by tumor cells is more powerful than vice versa, then this would constitute an ‘unfavourable’ situation for the tumor cells, which they try to overcome by secreting Ax in order to protect their nutritional supply. Assuming this to be the case, the purpose of secreting Ax would be to reduce the resistance of the normal cells and thus to impair their function. Hence, the ‘unfavourable’ situation for tumor cells can be equated to their poor nutritive situation. Since the nutritive situation of the tumor cells is variable, it follows that the secretion of Ax must occur discontinuously. Most probably, the nutritive situation during the avascular or diffusion phase is poor-equating to an ‘unfavourable’ situation (according to the hypothesis) which the tumor cells try to overcome by secreting Ax. The nutritive situation improves in the vascular phase (12). According to the hypothesis, this does not constitute an ‘unfavourable’ situation and thus the secretion of Ax decreases. After vascularisation and intravasation the elimination of most of the metastasising cells occurs in which the immune system participates (12). Thus, it would appear that the immune system is more effective in certain phases of the tumor process than in others. This leads to the assumption that the tumor cells are most effective where the immune response is most ineffective. In an improved nutritive situation, e.g. after vascularisation and ‘intravasation’, the immunologically competent cells are exposed to a far lower Ax-concentration. This results in a more effective immune response being directed at the tumor cells. If it were true that the tumor cells had to maintain the Ax-secretion in the intravascular phase as well, a response would have been expected similar to that of sepsis in the case of bacteriaemia, for instance. This

would imply ‘Tumorzellemie’ being more harmful for the host than metastasis. The Ax-effect on tumor cells-according hypothesis

to the

The effect of Ax might be either a selective influence on the normal cells, or a general one. The latter would entail the tumor cells needing to build up resistance against it. Since the biochemical differences between tumor cells and normal cells are only slight (34), a selective effect can probably be ruled out. If we assume that in the tumor cells a resistance is developed, the question then arises whether a growing resistance against Ax is not to be expected in the normal cells, too-which would be a perfectly logical conclusion. In view of this, the development of an apparent resistance arising from a critical Ax-concentration within the intracellular compartment seems to be more likely. The tumor cells show an increased fluidity (5) and a varied permeability of the cell membrane (1). And because of this, it is quite conceivable that increased production of Ax can result in a much lower Ax-concentration within the intracellular compartment of tumor cells than within those of normal cells. If fluidity and permeability were to increase with increasing dedifferentiation, this could LX interpreted as ‘evasive action’ against an impending increase in concentration within the intracellular compartment of the tumor cells which, in keeping with the hypothesis, could then be considered as an impulse for the dedifferentiation of tumor cells. These deliberations on the hypothetical existence of the substance Ax form the basis for the theoretical model presented below. Theoretical model

According to this model, the tumor growth is the resultant of several factors, as presented in the following form: GT - Tc.

[Ax],

1 $9 ,,C [Anti-Ax]

(I)

GT = growth of the tumor in particular tissue T, = number of tumor cells [Ax] = concentration of Ax in the tissue [Anti-Ax] = concentration of Anti-Ax in the tissue R = resistance of normal cells against impairment o&nction, dependent on the Ax-concentration Using a factor/time diagram, an attempt is made to plot the continuous curves of tumor growth under different conditions.

DISCONTJNUTY IN COWETITMZ

INTERACllON BElWEEN TUMOR CELLS AND HOST

Growth of a primary tumor During the initial stage-stage I-an interaction between normal cells and tumor cells occurs in which the tumor cells are at first inferior (41). The growth curve ought to show a gradual increase at this stage. The secretion of Ax gradually leads to an acceleration in growth. The section of the curve corresponding to accelerated growth is described as stage II. After the secretion of Ax has begun, antibody formation starts (Anti-Ax). This formation, by binding with Ax, results in delayed growth. The growth curve flattens out slightly during its course. This section of the curve is described as stage III. The increasing exposure of immunologically competent cells to the Ax-effect may result in a delay of antibody formation. This, however, would lead to a prevalence of free Ax, and thus to a renewed enhancement of tumor growth. The corresponding part of the growth curve is described as stage IV. At this stage the pre-conditions for the invasion of the tumor cells are set. According to the hypothesis, changes in the form of a dedifferentiation in the tumor cells are initiated by an increasing Ax-concentration. During the process of dedifferentiation, a reduction of desmosomes occurs (42), resulting in tumor cell dissociation. Dedifferentiation and dissociation are the pre-conditions for the invasion (11). The dissociated cells, having an independent locomotion (ll), destructively invade the tissue which encloses the tumor. This destruction may occur either in the form of pressure atrophy or encymatically. There are several different views on this matter. Some authors claim that rarefaction of the host tissue is the exclusive consequence of a progressing pressure atrophy (ll), others have concluded that a direct correlation bctween tumor size, mechanical pressure, invasion and metastasis does not exist (12). If the pressure of the growing tumor were to be of any importance to the invasion, the counterargument should also be discussed according to which pressure would be expected to be put on the tumor-corresponding to its size-by the tissue surrounding it. If this were the case, one could then assume that within a small tumor under lower pressure from the surrounding tissue, a more rapid dissociation of cells in the marginal area of the tumor occurs than within large tumors. The question to what extent an intense curvature of a very small tumor is of consequence for the intensity of dissociation in the marginal area, has to be left open for the moment. However, observations indicate that small tumors exerting very low pressure metastasise at an early stage, whereas

75

very large tumors exerting high pressure do not form metastases (44). In view of this, an encymatic, i.e. biochemical destruction seems to be more likely. Both the locomotion and the invasion of the dissociated tumor cells are-in relation to the primary tumor-centrifugal cell movements directed at the host tissue. The question arises why by hypothetical encymatic destruction, only the normal tissue is affected and not the tumor itself! In this context it should be noted that during the encymatic destruction of tissue in the case of clostridium histolyticum infection, all of the tissue around the puncture perishes (46). In view of this, it would appear to be more plausible that the destruction of the host tissue is bxwght about by a substance secreted by the tumor cells, corresponding to the Ax in accordance with the hypothesis. The observation that mutinous endometroid and clear cell carcinomata of the ovaries appear to be prognostically more favourable than serous carcinomata (22) can be explained-according to the hypothesis-by a ‘mucous barrier’ which protects the normal cells from Ax-very similar to the way gastric mucus is protected from intrinsic digestion (4). For, unlike normal cells which secrete mucus along the lumen, tumor cells excrete aimlessly (29). The observation that dedifferentiated tumor cells show higher invasiveness than better differentiated ones (11) can also be interpreted as being a consequence of the Ax-effect. If the increase in Ax-concentration, according to the hypothesis, initiates the dedifferentiation of the tumor cells in the marginal area, it is also likely that the Ax destroys the host tissue too, thereby enabling the invasion of the dissociated tumor cells. Should the dedifferentiated tumor cells reveal a higher invasiveness, this could be attributable to the fact that the host tissue is more ‘loosened’ by a hypothetical increase of Ax-secretion than in the case of better differentiated cells. This is probably comparable to the observation that invasive tumors possess an incomplete basement membrane (6). If it were true that the invasiveness of the tumor cells is not in any way dependent on the ‘intensity of the loosening’ of the host tissue, situations would be quite conceivable which could lead to a ‘uaumatization’ of the cells during the invasion, similar to intravasation. The consequence would be an elimination of the major part of the dedifferentiated cells and thereby a selection of better differentiated ones. After the tumor cells have invaded the host tissue, a short-lived proliferation and expansion (11) occurs.

76

MEDICAL HYFOTHEJ3E.S

This would suggest, in view of the considerations mentioned above, that an early occurring prolifemtion (in the stage of diffusion) followed by an invasion would be more likely to correlate with a higher malignity than one occurring later (in the stage of vascuhuisation). This might be a possible explanation for the different assessment of the proliferation towards malignity (12). Once the primary tumor has reached a certain size, another delay in growth occurs (40). According to the hypothesis, this could be explained by a decrease in Ax-secretion. This section of the growth curve shows an even course and is described as stage V. The general course of the growth curve corresponds to the observation that progressive phases of growth alternate with resting phases (41) and resembles a step function graph (Fig. 1). Spontaneousremission of tumors Spontaneousremissions in various human tumors (7) can be interpreted, according to the hypothesis, by antibody formation occurring relatively early (AntiAx). The secreted Ax is constantly blocked by the relatively high Anti-Ax-concentration. The growth of the tumor would thus be inhibited and this could then lead to an inactivation of tumor cells and finally to an involution of the tumor (Fig. 2). Factors:

Tc

Ax

anti-Ax

Growthof a tumor in patients withimmune insufficiency An increased susceptibility to cancer has been observed in patients with primary or secondary immune insufficiency (15, 32). According to the hypothesis, a poor antibody formation (Anti-Ax) is to be expected in a tumor-bearing, immune insufficient host, resulting in a relatively low blocking of Ax (Fig. 3). From this, it is evident that the probability of achieving a complete blocking of Ax in immune insufficient patients is less than in patients without any insufficiency. This might be an explanation for the above mentioned observation. Tumor growth in experimentalanimals treatedwith sera from animals that had recoveredfrom tumor disease When serum from mice that had recovered from tumor disease was injected into other tumor-bearing mice, this led to an inhibition of tumor growth, sometimes causing regression and an apparent cure (47). The serum which was taken in the recovery stage contained, in accordance with the hypothesis, a high Anti-Ax-concentration. This blocked the Ax secreted by the tumor cells and led to an inhibition of growth and regression (Fig. 4).

Rnc

*-

---_

___..a__.__.

Tc

_____,,,~~~~ ‘. \

_.--

l ;-y--L

/

I

1.

I

2.

I

3.

4.

15.

rtadlum

1

Fig. 1 Growth of the primary tumor as a step-function Tc = Number of tumor cells Ax = Substance seceming from the tumor cells anti-Ax = Humoral antibodies against Ax hc = Resistance of normal cells towards impairment of function depending on the Ax concentration

time

DLKONTKNUKY IN COMPEM

Factors:

77

INTERACTION BEIWEEN TUMOR CELLS AND HOST

Tc

Ax

antl-Ax

Rnc

.- _..-’ 1.

I

I

2.

3.

4.

15.

stadium

1

time

1

time

Fig. 2 Spontsnews regression of a tumor which greatly enhances the immune response Factors:

Tc

Ax

anti-Ax

Rnc

, 1.

1

2.

I

3.

4.

15.

stadium

Fig. 3 Tumor growth with an insufficient or suppressed immune system

Inhibition of growth in a retransplanted tumor . _

It has been shown experimentally that a tumor induced into an experimental animal could not continue to grow if it was excised and later retransplantcd into the same animal. But if the excised tumor was transplanted into a syngeneic animal, it would continue to grow (39, 49). According to the hypothesis, the

varied behavior of the transplanted tumor can be explained by a decrease of the Ax-concentration and thus a concentration-dependent, suppressive effect on the immunologically competent cells after the excision of the induced tumor. This led to a clear increase of antibodies (Anti-Ax). This high antibody-concentration permanently blocked the secreted Ax and thus

78

MEDICAL.HYWIXESES

Factors:

Tc

antl-Ax

Ax

RllC

antiserum

antl-Ax

.

-

__--

_----

Rnc

Ax’,

-I-1.

I

I

2.

3.

15.

4.

..Tc

stadium

1

time

Fig. 4 Regression of a tumor when treating the tumor-bearing-host with serum from animals that had recovered from a tumor disease, i.e. with serum containing anti-Ax

inhibited the tumor growth after its retransplantation (Fig. 5). The same resistance against the then retransplanted tumor became evident when the experimental animal was immunised with inactivated tumor cells after the tumor had been excised (24). According to the hyFactors:

Tc

antl-Ax

Ax

exclalon

pothesis, the Ax-formation ought not to be impaired by this. if the Anti-Ax-formation were to be rejected as being the cause of the inhibition of tumor growth within this context, the question must be asked why there is no enhancement in this case.

Rnc

reimplantation

anti-Ax

y--____--c---

.. \

\

l. \

Rnc

.. .. \ ‘. \ \ l. \ .. Ax\\,.*

1.

1

2.

1

Fig. 5 Regression of a rcimplanted tumor

3.

4.

15.

etadium

1

Tc time

DISCONTINUTY

IN COMPETITIVE INTERACl’lON

79

BETWEEN TUMOR CELLS AND HOST

Growth of a tumor with passive enhancement

If an experimental animal into which a tumor is to be transplanted is injected with serum from a tumorbearing animal, the transplanted tumor shows enhanced growth (23). Serum from a tumor-bearing host contains Axaccording to the hypothesis. Repeated injections of serum containing Ax result in an inhibition, that is a deceleration of antibody formation (Anti-Ax). After the transplantation of the tumor the secretion of Ax from a relatively great number of tumor cells begins. If the immune response is weakened, the Ax-concentration will increasingly prevail, resulting in an enhancement of growth (Fig. 6).

to an activation of the immune response which is directed at the cell membrane of the tumor cells, thus resulting in the destruction of tumor cells. The rapid increase of the Ax-concentration in the extracellular compartment leads to an inhibition of the immune response (Anti-Ax-formation) and thus to enhancement (Fig. 7); this produced the same result as the blocking serum-activity hypothesis (20). The inhibitory effect of cortisone on the enhancement (23) can be interpreted, according to the hypothesis, by the fact that cortisone inhibits the immune response which is directed at the tumor cells, and thus prevents massive destruction of tumor cells and secretion of Ax in the extracellular compartment.

Growth of a tumor with active enhancement

Interpretation of the behavior of certain tumors, according to the hypothesis, supposing an inhibition of the Ax-effect

If an experimental animal into which a tumor is to be transplanted, is pre-immunised with tumor cells, the then transplanted tumor will show a more enhanced growth than a transplanted tumor without pre-immunisation (23). If inactivated tumor cells in an experimental animal are inoculated for the purpose of immunisation, an immune response which is directed at the cell membrane has to be expected. According to the hypothesis, the reactions presented below are to be expected if the tumor is transplanted afterwards: the tumor cells are forced to produce Ax, if they are in an unfavourable nutritive situation after the transplantation. At the same time the pre-immunisation leads

If the tumor cells by secreting Ax try to reduce the ‘ability’ of normal cells to absorb nourishment, the question arises whether a ‘situation’ which reinforces the ‘need’ for nutrients of normal cells would intensify the threshold of sensitivity of Ax. This would lead to a deceleration of tumor growth. Hypoglycemia, for example, might correspond to such a ‘situation’. In this case, the tumors being accompanied by hypoglycemia would be expected to exhibit a delayed growth. Isled cell tumors, for instance, are accompanied by a hypoglycemia in various stages of fasting. These are mainly benign tumors. Only about 510% are malignant ones (25).

Factors:

Tc

Ax

antl-Ax

Fl nc

serum Implantation

I

I

)/--

--

Ax

_H

time

Fig. 6 ‘Passive’ enhancement of the implanted tumor after immunization with serum from tumor-bearing animals (serum containing Ax)

80

MEDICAL HYKYI’HESES

Factors: lnoculatlon Inactivated I tumorcells

Fig. 7 ‘Active’ enhancement

Tc

Ax

anti-Ax

Rnc

of

of the implanted

nunor after immunization

The majority of gastrinoma are malignant tumors. Malignancy may be less with gastrinoma of a multiple adenomatosis type I (25). According to the hypothesis, it may be presumed that given isled cell tumors inhibit with hypoglycemia the development of malignancy of gastrinoma. In addition, tumors are to be mentioned which are not pancreatic, insuline-producing or classifiable into certain types, such as fibroma, fibrosarcoma, spindlecell sarcoma or leiomysarcoma (the most frequent ones). These show very slow growth and do not form metastases (2, 38,48). From the report on hepatocellular carcinoma accompanied by hypoglycemia (31) which is based on histological results, one can gather that tumors showed a poor differentiation in patients with mean duration of illness of 3.5 months (range l-6 months) as against a good differentiation in patients with mean duration of illness of 7 months (range 2-36 months). It was striking that hypoglycemia occurred 2 weeks before exitus in patients of the first group, but 2-10 months before exitus in patients belonging to the second group. According to the hypothesis, this reveals that not only the hypoglycemia, but also the momentum of its occurrence is of consequence for the tumor’s development of malignancy. Metastasis process The metastatis process-from the vascularisation of the tumor and intravasation to extravasation-is im-

with inactivated

tumor cells.

portant in that it produces the pre-condition for metastasis formation. This depends on a critical number of cells (45) which is the result of cell production and elimination (40). It mainly occurs by mechanical burden (12). If the process of elimination leads to heavy losses of the tumor cells, so that metastasis formation is considered a rare phenomenon (19), this presumably arises from clear differences between normal cells and tumor cells. With heavy losses of metastasising cells under mechanical burden one may assume that the membrane system of tumor cells, e.g. cell membranes, is particularly sensitive. The intensive synthesis and degradation of cell surface proteins within the cell membrane of tumor cells (35), as well as the increased mobility of membrane components (l), could be considered as a possible cause for a poor resilience of the cell membrane of the tumor cells. If cellular structures, such as cell membranes of normal cells, for instance, are damaged in a certain ‘situation’, it can be assumed that, within the prestage of such a ‘situation’, the corresponding structures of tumor cells, but not of normal cells might be damaged. Such ‘situation’ is for example present with shock, in which among other things membrane lesions of hepatocytes which predominate in the early phase of shock are to be found: (Liver)-membrane destructions in the single cell of surface epithelium (gastric duodenum)-minor destruction of the mem-

DISCONTlNUTY

IN COMPETlTWE Ih’TEXACllON BETWEEN TUMOR CELLS AND HOST

brane and swelling of mitochondrium in A and B cells Panc=a@ (10). Since shock and its intensity are dependent on the secretion of histamine and the extent of secretion (16), one can derive that the coincidence of tumor and some other illness correlating with a frequent secretion of histamine might be slight. This might be the case with bronchial asthma which is connected with a secretion of histamine. A ‘dystrophy’ between bronchial asthma and cancer has been detected; ‘dystrophy* representing a relation of two diseases being mutually exclusive (28). ‘Dystropy’ could be explained, according to the hypothesis, by a frequent occurrence of ‘situations’ in the course of an illness (bronchial asthma), resulting in an irreversible damage of the cell membrane of the tumor in connection with its poor resilience. The consequence of this would be an inhibition of tumor growth, i.e. a regression.

Metastasis formation

Once the tumor cells have reached the extracellular compartment of their target organ, a growth retardation occurs, which comes relatively soon after an initially high activity of proliferation. This can be seen as the equivalent of so-called tumor dormancy, or resting micrometastasis (12). The resting micrometastasis seems to represent a state of equilibrium between opposed factors, metastasis formation not occurring until this is upset. Failing this, one would expect that a micrometastasis formation (resting metastasis) would turn into a manifest metastasis within a relatively short time as the result of so-called ‘sneakingthrough’ (43). The short-lived proliferation following extravasation is attributable, in accordance with the hypothesis, to nutrients which have reached the extracellular compartment along with the tumor cells. The nutritive situation deteriorates as a conseqeunce of the nutrients being consumed, and the tumor cells respond by secreting Ax. However, the Ax is blocked by the existence of anti-Ax. Further proliferation is inhibited, resulting in a resting metastasis. If, for some reason, there were to be an increase of secreted Ax during resting metastasis (micrometastasis) of an organ, this would lead-according to the ‘relation of factors (I)‘-to an imbalance and would thus initiate the growth of the resting metastasis. An increase in the secretion of Ax, though, may also upset the balance of other resting metastasis in a similar way and initiate growth elsewhere. This spread of ‘activation’ from one metastasis to another could start a chain-

81

reaction, turning the re3ting metastases into manifest ones. Many different metastases secmting Ax at the same time would increase the toxic effect and impair the function of the host with all its inherent consequences. In view of this, the early recidivism (e.g. scar recidivism) can be interpreted as being a manifestation of resting tumor cells, whose growth is initiated due to the decreased resistance of normal cells in an irradiated area and a lower Anti-Ax-concentmtion within the scar tissue. The following case might be taken as an example: a %year-old patient received deep X-ray therapy for a radical mastectomy. Three years previously she had had a malignant melanoma removed from her right foot, with no evidence of local recurrence or metastasis formation. Within a few weeks following mastectomy and X-ray therapy there were thousands of subcutaneous melanomatous nodules and metastasis in the irradiated area which had developed in other organs (46). It was concluded that either the operation, or the radiotherapy-or both-had been the cause of the tumor-host relationship becoming disturbed (50). leading to the assumption that the host possesses defense mechanisms which are effective against existing tumors (47). The late recidivism may result from resting tumor cells (41). According to the hypothesis, an increase of Anti-Ax-concentration arises after the tumor resection and inhibits growth of the tumor cells. After a certain period of time and with the severe decrease of AntiAx-concentration, the free Ax prevails, resulting in tumor growth. In contrast to the primary tumor, the growth of the recidivism starts at the second stage with a larger number of cells than at first stage. The heavy increase of Ax-concentration inhibits the reactivation of the immune response. 0rganantilrop)r’nterpretation

When forming metastasis, cells of a certain primary tumor prefer certain organs. This phenomenon is called organouopy (12). But one could also say that some organs, or rather tissues, are able-in relation to the primary tumor-to inhibit a metastasis formation within their own tissue. This would indicate an existing organantitropy-factor. Its effect on the tumor cells could be described for example as ‘repulsive’ or inhibitory. This would mean that an organantitropyfactor would ‘divert’ the metastasising cells from the target organ or inhibit their proliferation. In 1955, it was observed that until then little had been written about metastasis formation in the vegetative nervous system (21).

82 From 3317 autopsy cases arranged into 34 classes of primary tumors, only the primary tumors belonging to the class of skin melanoma formed nervous metastasis (36). Considering the hypothetical existence of an organantitropy-factor in connection with the observation that the prognosis is improved by the appearance of neural tissue in teratocarcinoma, it seems that, if delayed tumor growth is based on the improved prognosis (37), the effect of the organantitropy-factor on the metastasising cells could be explained as a better differentiation with inhibitory proliferation. Concepts for prophylaxis and treatment in accordance with the hypothesis a) Immunological view. To prove and isolate a sub-

stance corresponding to Ax would constitute the precondition for an active immunisation which, considered as a prophylaxis, would not have the purpose of inhibiting the appearance of a tumor, but rather of blocking its growth within the phase of diffusion. The attempt to isolate the substance Ax must be made in the phase of diffusion, because, according to the hypothesis, the secretion of Ax is peculiar to this phase of tumor growth. Through binding Ax, the inhibition of tumor growth in the phase of diffusion, as well as the blocking of enhancement with the immunisation of the tumor-bearing host with tumor cells, could be accomplished with passive immunisation-as treatment-by using a serum containing Anti-Ax. A two-step immunisation is necessary, according to the hypothesis, to produce an antiserum. The supposition that serum from a tumor-bearing host which leads to an enhancement with immunisation (see passive enhancement) necessarily contains Ax, leads to the conclusion that first of all a second host has to be immunised with serum in order to obtain an antiserum.

MEDICAL EIYRXEWES

Blocking of metastasis formation by a possible organantitropy-factor would result in an inhibition of proliferation of metastasised cells, regardless of their heterogeneity. If the organantitropy-factor were secreted from nerve cells-which can be derived from the examples above-the effect of a substance like, e.g. acetylcholine which is synthesised in nerve cells (terminal neuroma) (18), could be important from a phylogenetic point of view. According to this, protozoa-having achieved the highest differentiation possible (e.g. Paramecium caudatum)-possess acetylcholine and adrenaline, whilst other less differentiated protozoa follow a different biochemical path (8). From the ontogenetic point of view, it is claimed that acetylcholine and acetylcholinesterase function as embryonic inductors of the nervous tissue-experiments on chicken embryos are taken as examples (9). In both cases acetylcholine is connected with a higher differentiation, that is the induction of a higher differentiated tissue. From this, a differentiation-inductive effect of acetylcholine could arise which could lead to an inductive differentiation within the tumor cells and thus to an inhibitory effect on growth, since an increase in differentiation is synonymous with inhibited proliferation (13). d) The aspect of hypoglycemia. The above mentioned tumor cases reveal a connection between hypoglycemia and a delay in tumor growth, whereby the precise time hypoglycemia makes its appearance may be of consequence. Whether hypoglycemia should be considered as a possible therapeutical measure, would have to be discussed.

b) The aspect of mechanical resilience of membrane systems. If the heavy loss of tumor cells under me-

Concepts to locate the target of the hypothetical substance Ax

chanical burden (12) were based on a low resilience of the cell membrane of the tumor cells, such a difference between tumor cells and normal cells could serve as a basis for therapeutical measures. The purpose would be to examine the effect of substances which can lead to an irreversible destruction of cell membrane with poor resilience-following the observation that surfactants like, for example, octylamines or decylamines in a relatively high concentration lead to extensive destruction of the cell membrane (17). c) The aspect of a possible organantitropy-factor. The heterogeneity shown by the metastasising cells of a primary tumor leads to some problems in therapeutical measures (22).

If it is true that the tumor cells, according to the hypothesis, impair the function of normal cells by secreting the substance Ax in order to protect their ‘need’ for nutrients, we still have to find its actual target. It seems that, according to the hypothesis, a cell has to synthesise its own substances. Therefore, this necessity determines that nutrients are needed, and the need for nutrients determines the intensity by which the nutrients are absorbed by the cell. The target of Ax would therefore be to slow down the synthesis of normal cells by reducing the need and the intensity of nutritional absorbance, in order to obtain a larger amount of nutrients for the tumor cells.

DLSCOXWNUXTYXN COMPBTXTXVE INTERACX’XON BBlWEEN TUMOR CELLS AND HOST

The tumor-bearing host is in a catabolic state which is connected with the symptom ‘anorexia’ (41)-anorexia representing a reduced need. If the necessity for an intrinsic synthesis within the normal cells of the tumor-bearing host were stimulated by a situation and the need for nutrients were reinforced, the Ax-effect would probably be suppressed-according to the hypothesis. This would lead to a decreased sensitivity of normal cells towards Ax and enable the immunologically competent cells to prepare a more effective immune response. Hyperthyroidism corresponds to this situation, according to the hypothesis. In this case, there is a catabolic state with protein metabolism which is combined with the symptom of ‘increased appetite’ (14), which represents in increased need for nutrients. In light of this, note should be taken of the only slight coincidence between carcinoma and hyperthyroidism (33). There is a different situation with chronic renal insufficiency. The catabolic state is here combined with the symptom ‘anorexia’ (3)-anorexia representing a reduced need for nutrients. According to the hypothesis, the retention of substances in urine which ought to be excreted could lead to a deceleration of the intrinsic synthesis of the normal cells-like a feed back-and thus to a reduced need for nutrients. This would imply the existence of a synergism between substances usually eliminated with urine and Ax, a concept supported by the high coincidence of carcinoma and chronic renal insufficiency (30). The substances which are retained in chronic renal insufficiency stem from protein metabolism. Carbohydrates and fat are burned to CO2 and Hz0 (3). The hypothetical feed-back effect of retained substances would therefore affect protein synthesis. Due to the assumed synergism of retained substances in chronic renal insufficiency, it would appear that protein synthesis emerges as the target of Ax. If, however, the effect of Ax-presumed above-were to lead to a deceleration of protein synthesis in the normal cells, this would result in a decreased ability on the part of normal cells to absorb amino acids and, subsequently, to a higher ‘quantity’ for the tumor cells. Moreover, according to the hypothesis, it can be assumed that amino acids are of particular importance to the tumor cells. This is illustrated by the way the tumor cells prevent amino acids from being absorbed by the normal cells. If this were considered to be feasible, it ought to be made the subject of further investigation.

83

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