As diverse opinions are held about the significance of systemic influences in cancer, the subject needs some reconsideration. What are “systemic influences”? In the literature on cancer this preliminary question is usually ignored, presumably because it is thought that the answer is self-evident. With this view I do not agree. I think one must begin by forming a general conception about the nature of systemic influences. What are they like in the normal body? What is their position in bacteriological immunity, about which knowledge is more advanced than in cancer? Ideas derived from a discussion of these two questions ought to provide a useful base for approaching the problem as it concerns malignancy.

In the normal body the systemic influences which the plasma exerts upon the tissues form a complex system presenting three aspects, the chemical, the chemico-physical, and the vitalistic. For example, sometimes it may be said that the plasma's activity is due to a special chemical substance, such as a hormone; sometimes the predominant factor is due to the balance of its colloidal constituents; and not infrequently its action can only be attributed to those properties of living matter which cannot be reproduced in the chemical or the physical laboratory. These three aspects of systemic influences are not independent factors but have to be correlated; and the essential difficulty of the subject is to assign to each of them its appropriate significance.

In natural immunity and resistance towards bacteria, these normal systemic influences are in possession of the field and it is upon their activities that the fate of the bacterial intruders largely depends. Where the immunity is non-specific, as in the inability of saprophytes to grow in living tissues, the defensive factor bears a prominently vitalistic aspect. The mechanism of bacterial destruction seems largely to depend on the circumstance that the bacteria find themselves in a living animal environment where they cannot remain in the resting stage; they must endeavour to grow but they perish in the attempt because the medium is unsuitable.

What is the nature of “alexin” as a natural defensive mechanism? The idea that it is a special chemical substance secreted by some cells of the body must be abandoned. In vitro, it is a property due to the chemico-physical lability and colloidal complexity of fresh serum, in virtue of which the serum promotes interactions which would not take place in a more stable medium. In vivo, the plasma possesses similar chemico-physical properties in a more complex and more effective form, supplemented by its vitalistic capacities as living material. For these properties of the circulating plasma the term “alexin” is not appropriate.

As regards specific manifestations of natural immunity, how is one to explain the selective action of normal systemic influences on bacteria which are pathogenic for some species of animals but not for others? Selection naturally suggests special chemical attributes of the plasma; but species immunity has not been identified with the presence of distinctive chemical substances and it is not likely that it ever will be. One has to fall back on the chemico-physical attributes of the plasma which constitute its general “make up,” as characteristic of a particular species. And these attributes must be regarded not as a system in stable equilibrium but as a dynamic system involving an ordered sequence of reactions.

The most important feature of true natural immunity is that, when the bacteria have been disposed of, the condition of the plasma remains as it was before their intrusion. Its activities have not been due to antibodies, in the accepted serological sense, and the destroyed bacteria have not behaved as antigens.

In most of the literature on acquired immunity the chemical conception stands out very conspicuously. Bacterial protein behaves as an antigen and stimulates certain cells of the host to secrete an antibody; that is regarded as the basis of immunity. After allowing for the operation of chemico-physical laws, the predominant feature remains that an immunological reaction is essentially the interplay between two chemical entities, an antibody (agglutinin, lysin, tropin, etc.), and its corresponding antigen. This conception is considered preferable to the much less concrete ideas of interactions between systemic influences and living bacterial protoplasm.

Whilst appreciating the value of precise chemical data, I consider that this view of acquired immunity is one-sided and inadequate. Systemic influences (other than serological antibodies) cannot be left out of account in the conception of interactions between living bacteria and the living animal body. One needs a scheme which will help to correlate natural with acquired systemic influences, to bridge the gap between specific and non-specific factors, and to modify the conception of an antibody as a special chemical entity, specially secreted by certain cells in response to the stimulus of a foreign protein. Within such a scheme, as I have endeavoured to show, an explanation may be found for what may be called the routine production of antibodies by antigens.

Coming now to cancer, one must first insist on the commonsense view that the transplantation of grafts is a special and relatively unimportant line of experiment which, whatever interests it may possess in other respects, does not help to explain either established autogenous cancer or the genesis of cancer. In these grafting experiments certain systemic influences emerge which cannot be explained as due to the production of antibodies by antigens. This is to be expected, on the analogy of similar manifestations of antibacterial systemic influences. But neither natural nor acquired systemic resistance to the taking of a graft involves anything which may be regarded as a new kind of systemic influence peculiar to cancer.

In the case of established autogenous cancer there does seem to be a new kind of systemic influence which is directly attributable to the disease. This influence, as is found by animal experiment and by observation on human malignancy, inhibits, or tends to inhibit, the creation of a second and independent malignant growth in the same animal body. Apparently products of the existing cancer pass into the circulation and cause other tissues to lose their susceptibility to influences which might ultimately have produced a malignant variant. The mechanism of this inhibitory action is obscure and is probably more complex than the chemical influence of a particular cancerous product upon normal cells. Whatever may be the right explanation, the observed facts indicate that it is something new, which is created by the cancerous condition; they afford no proof whatever that, before the cancer existed, there were in the circulation special systemic influences which were favourable or unfavourable to the genesis of cancer.

The idea that there are systemic influences concerned with the genesis of cancer has assumed many forms and is often expressed ambiguously. Does it mean that normal cells have a “natural tendency” to malignancy and will actually become malignant if freed from systemic control? I do not accept this “natural tendency”; unrestrained growth does not suffice to explain the origin of cancer. What is meant by “systemic control”? My view is that such control regulates normal cells and that cancer cells are independent of it; I do not agree that there is a special kind of antimalignant systemic control which may destroy the fully fledged cancer cell. What is the nature of “susceptibility” to the change into the cancerous condition? I regard it as essentially a cellular property, not as a humoral or systemic influence, though I admit that irritant material which gains access to the circulation may increase the susceptibility of particular cells. What is meant by “resistance” (either local or systemic) to cancer? Owing to the recuperative powers of the animal body, local disturbances of metabolism are often corrected and there is a return to the normal condition; some of these disturbances, if left uncorrected, might have led to cancer and the fact that they have been corrected may, if one likes, be called resistance to the genesis of cancer. It is also known that true cancerous foci or metastases may remain quiescent for a considerable time. But I do not agree that such quiescence has been shown to be attributable to a specific kind of antimalignant “resistance” (either local or systemic).

Whilst there is no satisfactory evidence, either direct or indirect, of a systemic influence which causes cancer, systemic influences are so complex and obscure that this possibility cannot be definitely excluded. But there does not seem to be any cogent reason for dissenting from the view that the production of the malignant variant is due to its local environment.