I propose here that cancer, similarly to most diseases such as cardiovascular, autoimmune and neurodegenerative diseases is simply, in most cases, the final expression of an early or late derangement of central neuro-endocrine-immune control, defined now as ‘immunological surveillance’, leading to a loss of non-proliferative control of pre-existing and “dormant” pre-neoplastic or neoplastic cells in the body.
The ‘hormonal-immune’ alteration preceding and anticipating onset of cancer, does not depend only on a chronic quantitative changes of hormone synthesis and release, but on a de-synchronization of their rhythmic, circadian release, in which the pineal network plays a major role. Being the immune system totally controlled by the circadian, day-night cyclic periodicity of hormones, the resulting alteration of hormone rhythms leads to a veritable destruction of the capacity of the immune system, not to eliminate, but to keep emerging tumor cells under non-proliferation control.
Malignancy is simply the obvious outcome of chronic alteration or absence of hormonal rhythms which strictly control the maturation and the activity of the thymo-lymphatic, immune system. Dilman’s vision is thus here confirmed and extended. This approach allows now to proceed to cancer prevention with a simple and efficient monitoring of those physiological hormonal values which must be maintained and express precisely the existence of a central ‘pineal life clock’ related to reproductive and immune functions and to the pineal program of aging.
Alternative therapy approaches are also suggested for advanced, non curable and metastatic cancer by using a novel method for xenogeneic (between different species) bone marrow transplantation.
I wish to dedicate this article to the memory of my close scientific and family friend Vladimir Michailovic Dilman from Saint Petersburg, one of the greatest Russian scientists, a unique and unforgettable person, scientist and human being, with whom I shared for many years the conviction, now a reality, that aging and consequently aging-related diseases can be interpreted, understood, prevented and cured. We were both convinced that the ‘aging syndrome’ initiates and progresses in the central nervous system and in the neuro-endocrine nuclei which monitor and modulate hormone synthesis and release. We shared the view that early and late control of such essential life functions makes feasible interventions apt at producing a true regeneration of basic hormonal functions in the brain and a more juvenile condition, even at a later age. To my question “Do you think that aging is reversible? “ He answered with a firm: “No doubt about it!“ I have been sharing this view since I read his article on Lancet (Dilman, 1971) and started a correspondence with him.
Vladimir Dilman possessed such a human and scientific dimension that his life remains for me a legend, a mystery and a tale. In fact, for almost his whole life he was forced by the Soviet System to work and survive, in spite of his recognized and undeniable geniality, under incredibly humiliating and difficult conditions. I was personally experiencing it, when I visited him at the Petrov’s Institute in 1987, trying to force the managers of the Institute to accept my invitation to him, sent in 1986, to attend the First Stromboli Conference on Aging and Cancer. I still remember the face of a lady at the Petrov’s Institute, wildly shouting at me when I protested their denial of the permit to attend the Conference. In fact, he also was surrounded by mean and envious colleagues. At that time we used to talk to each other while walking for hours along the river Neva! He was afraid of spies and wanted to avoid problems for me, in spite of his courage to take me in his flat with no permission a few years later. The fact that he was Jewish was certainly not irrelevant in his case.
My discovery was the inevitable consequence of Dilman‘s logical thinking (Dilman, 1971, 1978, 1986 a,b, 1991; Revskoy et al., 1986). His view has always been in harmony with mine, not only because of our reciprocal esteem and trust, but also like a magical premonition of the inevitability of Nature‘s cosmic laws. He was my ‘Anti-Epictetus’, erasing my constant doubts that I may be wrong!
Unfortunately ‘Nemo propheta in patria’ applies to Russia too. His country has willingly ignored the greatness of this scientist and the political system in which he lived almost his whole life has suppressed the immense potential, also economic, of his research in cancer and aging. In fact, criminal political organizations and parties are also exquisitely stupid!
I strongly wish that Vladimir Dilman and his gigantic scientific achievements are not overlooked and forgotten. Their values immensely exceed the mediocrity surrounding us. Men like Vladimir Dilman are amongst the very few constantly and silently supporting our faith for a dignified and worthy life. I deeply miss and regret his absence and bear with me a tremendous nostalgia of his world presence.
In purely medical and immuno-biological terminology, cancer can be defined as the onset and quantitative visibility in the living body of anomalous cell elements possessing a degree of autonomy deeply different from tumor to tumor in the meaning that they, both from the metabolic as well as from the immunological viewpoint, can be distinguished from the normal cells of the tumor-bearer and represent therefore an intruding ‘foreign body’ which escapes the immunologic and metabolic non-proliferation, inhibitory control (Pierpaoli, 1981). With other words, and certainly by simplifying, tumor cells possess or have progressively acquired a high degree of autonomy and are thus able to replicate themselves outside the immunological and metabolic “rules” regulating all normal cells of the body.
Tumor cells are or become, in the course of the progressive malignant transformation, more and more independent and in some way ‘simpler’ and less demanding in their energy-producing oxidative mechanisms (Warburg, 1923; Pace et al., 1967). In addition, they change their identity and from elements which can be recognized by our immune system as ‘self’ and thus ‘own’, they become ‘non-self’ or ‘different’ and by this way they escape more and more from immunological control, also called ‘immunological surveillance’ (Pierpaoli, 1981, 1985 a,b).
In spite of that, at least theoretically, ‘de-differentiation’ of tumor cells should result into a higher antigenic ‘diversity’, and consequently to a higher immune reaction promoting a rejection of the tumor cells, in fact the opposite phenomenon takes place and ‘malignant’ tumor cells become practically ‘free’ and torn off the body, similarly to a parasite which feeds itself of ‘living food’ belonging to the body of somebody else, carries on an autonomic life, and escapes immunological defenses with diversified and sophisticated methods.
The tumor is truly an uncalled-for guest, which accepts small amounts of simple food, uses little oxygen in the ‘room’, but progressively and sometimes slowly and inadvertently, silently invades the house (the body) and then suddenly behaves as the house-lord! This event is wrongly perceived and seen as ‘new’ while, on the contrary, more or less ‘quiescent’ or ‘dormant’ tumor cells have always been hidden and present in the body, for example in the bone marrow, but could not replicate and give thus origin to a tumor (Pierpaoli and Haran-Ghera, 1975, 1977). Therefore the origin of cancer is certainly due to the sudden or progressive alteration and then the breaking off of a central non-proliferation control, which I have identified in the neuro-endocrine-immune system (Pierpaoli and Sorkin, 1968 a, b; 1972 a-d; Pierpaoli et al., 1974, Pierpaoli, 1985a). Experience acquired in the medical integrative discipline now known as ‘neuroimmunomodulation’ (NIM) (Jankovic et al., Eds., 1987; Spector, 1988; Fabris et al. Eds., 1994), prompts us to believe that the primary cause of the alteration affecting the central physiological control for tumor non-growth (immunological surveillance) is a genetically acquired or induced disposition further enhanced by a hormonal derangement in a broad sense, which results into a deficient immunological, inhibitory, non-proliferation control of tumor cells. However, I think that the immunological section is always an element secondary to the neuro-endocrine derangement, as we have shown in many experimental models and as is also evident in a large variety of clinical observations (Pierpaoli et al, 1977; Pierpaoli and Meshorer, 1982; Pierpaoli et al., 1988).
This fact explains also the reason for the initial hormone-dependence of many non-malignant tumors (or with a low degree of malignancy) such as those of reproductive organs (uterus, prostate, ovaries, and mammary glands) and endocrine glands (thyroid, testes) which are regulated by precise hormonal cycles. I do not believe at all in the efficacy of a suitable ‘immunotherapy of tumors’ because it can be considered only in the context of a strategy based on the understanding of the primary causes which have led to the primary „immunodeficiency“ anticipating the onset of a tumor! In my view, tumor therapy must be based on scientific logic deriving from our knowledge of physiology and pathology of the normal tissues and organs, namely ‘the knowledge of the non-cancer’, which is the neuro-endocrine regulation of the oxidative metabolic pathways for the replication of normal cells, which is based on a myriad of largely unknown elements (Pierpaoli, 1981).
Our lack of integrative knowledge of cellular and organ regulation (homoeostasis) (Pierpaoli, 1985a, b) compels us to empirically anticipate therapeutic trials which can prevent cancer, to keep it under non-proliferation control in its early phase, and finally to eradicate it totally with a massive attack when all other prevention and control therapies have failed. However, I am personally convinced, similarly to Dilman (1978, 1981), that it is already now possible to prevent neoplastic diseases with an adequate protection, by maintaining the integrity of the neuro-endocrine system and the splendid biologic rhythms which are the basis of health. We have again ‘rediscovered’, after millions of years, the obvious existence of a ‘biological health clock’ (Pierpaoli and Regelson, 1994) and we can now make use of it with no risk! The dramatic delay in the application of simple and effective therapeutic NIM measures in cancer therapy offends the criteria of scientific logic and the interest of the patients. This delay is only based on vested speculative attitudes, lack of research funding and the devious alibi that it is not possible to produce clinical data in man within two-three years! Only noxious drugs are investigated with huge funding, proposed and applied!
This attitude has prevented patients from being cured with alternative non-aggressive methods over a long period and with public funding. This business attitude will find its end at the end of clinical studies now in course, which will indicate, not only the way to prevent the onset of tumors, but also how to age with no diseases (Regelson and Pierpaoli, 1987; Pierpaoli and Regelson, 1995). In this strategy I include phases in the fight against cancer, which can be divided as follows.
If genesis of tumors depends on the pre-existence or acquired inadequacy, in early life or in the course of aging, of the neuro-endocrine control of physiological functions of all organs and tissues, I believe that the maintenance of hormonal circadian (day-night) rhythms is fundamental for tumor prevention Pierpaoli and Sorkin, 1972a-d; Pierpaoli et al., 1974). Interventions now applied for maintenance of the hormonal synchronicity of all body functions according to the solar-planetary, circadian, lunar and seasonal rhythms, allow us to re-synchronize all neuro-endocrine functions and thus consequently also of all immune functions in a broad sense, to the extent that, in spite of the fact that there may exist very severe alterations of hormonal rhythms even in young people, a neuro-endocrine check-up will allow us to anticipate with a large margin of time, the incipient onset of a tumor ( Pierpaoli and Sorkin, 1972 a, b).
The consideration of a ‘perfect health condition’ is highly misleading, since our society has allowed the survival of a very large number of people who would not survive in the life conditions of a century ago. They carry obviously hereditary and acquired flaws and a tendency to develop any kind of disease even at a young age. Therefore the monitoring of the integrity of the hormonal and rhythmic system with routine methods, should be systemically applied from a young age at 6 month-1 year intervals, aiming at discovering in due time those neuro-endocrine derangements and unbalances of daily hormonal rhythms, which anticipate precisely the onset of a tumor and are its direct cause as a consequence of immune alterations of all kind produced by the loss of the hormonal control of immunological surveillance (Pierpaoli and Sorkin, 1972a-d; Pierpaoli et al., 1974; Pierpaoli and Haran-Ghera, 1975, 1977).
The possibility to gradually or rapidly restore biological rhythms of synthesis and release of all hormones with exogenous intervention is the basis for prevention of tumors at all ages. The discovery that aging is a ‘program’ inside the ‘pineal network’ of the brain (Pierpaoli et. al., 1991; Pierpaoli, 1991; Pierpaoli, 1994; Pierpaoli et al., Ed., 1994) allows now us to restore again a body balance both from the hormonal and the immune viewpoint. This method is impressively simple, but it requires a basic physiology education which few possess, and many even foolishly boast not to see, physicians and specialists included! It is absolutely clear that the exogenous, late evening administration of Melatonin is, at this stage, the sole and irrefutable basis for tumor prevention (Narita and Kudo, 1985; Regelson and Pierpaoli, 1987; Lissoni et al, 1988), together with other adjuvant but non determinant elements such as nutrition (not diet), sleep and mild, daily physical exercise and a relatively ‘healthy’ environment.
We must now better identify those elements of the pineal gland which take part in the maintenance of circadian rhythms and are able to accelerate and restore the biological re-synchronization of the body.
What would you do if cancer would hit you or a person close and dear to you? This question does not expect a precise and convincing answer, but it puts me in a condition where I must do all possible for an honorable proposal! In many cases the removal is proposed of a presumably primary tumor and a second intervention of ‘cleaning’ with various and always ‘new’ chemotherapy drugs, assorted and selected according to the caprice and fashion of the recommendations and schedules of drug producers and daily oncology research.
In the case of radiosensitive tumors, which are predominantly non-malignant, expansive but not infiltrating, local radiotherapy is rightly applied. Unfortunately, radiotherapy is often producing severe immediate or late damage of normal tissues close to the tumor. The decision on the therapy depends on the patient, but in fact it is up to the physician known to, and presumably respected by the patient.
The surgical removal and treatment of a more or less ‘benign’ tumor concern a wide category of systemic or localized tumors, and this surgical procedure cannot be discarded a priori. In fact, a great number of the so-called ‘treatable’ tumors can be successfully treated (and brought to final healing) with different interventions, including those blindly accepted by ‘modern’ medicine. However, the unlucky problem is that surgical interventions and the following drug treatment intended by the oncologist to eradicate any trace of residual tumor cells are highly noxious for health and the psychosomatic integrity of the patient. Those treatment-produced derangements inevitably lead to an impressive number of neuro-endocrine, immunological, psychic alterations which obviously result frequently into tumor relapse and a higher malignancy resistant to any kind of treatment! On the contrary, in my view, onset of a treatable and non invasive tumor of low malignancy is only a symptom of a possible disease, an ‘“important message’, an alarm signal which our body delivers to us in order to make us aware of a deficient health condition often generated by remote, congenital or environmental causes, which have escaped our attention and can be attributed to complex socio-economic and familiar situations (Fox, 1982, 1988) and even to the cruel ‘natural genetic selection’.
The question is invariably: “why should it happen to me?” Therefore we must learn to consider a benign tumor, if not as a friend, as an ambassador bringing to us alarming, but not catastrophic news, making us aware and alert in due time of a condition of danger in our body. My strategy is to work on the anticipation of the time needed for the tumor to grow further and deviate to malignancy and become invasive and anaplastic. I anticipate with preventative measures the evolution of its extraordinary ability to escape and abrogate ‘immunological surveillance’. With other words, we must interpret and then correct the peculiar and tumor-enhancing biological basis which has allowed the onset and maintenance of the tumor, namely a congenital or acquired deranged neuro-endocrine (hormonal) system, induced by a variety of causes which is practically impossible to anticipate early enough.
We must examine carefully the neuro-endocrine values and their rhythmic stability with all available means (laboratory assays, symptoms, family story etc.) and apply then all procedures apt at re-equilibrating and re-synchronizing hormonal values when we detect or only suspect that a hormonal deficiency is present. This concerns not only maximal or minimal values, but principally an imbalance of inter-hormonal relationship and in particular, and here is the basis of our preventative and therapeutic proposal, in the re-acquisition of circadian periodicity and synchronicity, which is the basis not only for health but also for the genesis and progression of aging, of degenerative diseases and of cancer (Lapin, 1976; Revskoy et al., 1986; Dilman, 1986).
The initial “shock therapy” and its maintenance in time are a part of a ‘planetary’ physiology concept which allows us to tune up our body to the basic laws of circadian and seasonal rhythms. The practical and clinical-therapeutic strategy which we will follow is not a part of this essay. It is based on my first timid attempts at preventing aging-related diseases. These interventions are linked to the use of endogenous, natural agents and minerals which are an integral part of our biological and biochemical frame and structure. Tumors must be kept under non-proliferation control and possibly eliminated by adopting a veritable encircling ‘siege’ strategy, where our moves are intended to restore as fast as possible, in the cancer-affected patient, a condition of central and peripheral neuro-endocrine and consequently psychic and immunologic balance.
We must radically modify our view of degenerative and tumor diseases. They are simply the outcome of acquired or induced deviations of our centrally-regulated hormonal system in the sense intended by Dilman (1971), which is perfectly amenable to be adjusted again by delivery, acquisition and maintenance, even with pharmacologic agents, of central synchronic messages which are generated in our “central clock” of the hypothalamic-pituitary-pineal network, which are basic for maintenance of a body, biologically synchronized to the natural rhythms which are proper of a neuro-hormonally healthy person. We must tune back the brain to the planetary laws! If we ignore the possibility that our nervous system may recover again the ability to record and deliver the precise signals and impulses of natural rhythms, and transfer them to the myriad of elements and cells of the body, it would be illusory to arrest the growth of an initial tumor with single ‘hormonal’ therapies which can only haphazardly repair the apparent deficiency of one hormone, but producing at the same time severe side-effects, as it is almost invariably the case, as an example, with the infamous cortisone, one of the most popular immunosuppressive ‘killers’ of medical practice.
We have thus identified in the pineal network the ‘spider’ controlling the complex hormonal web, constantly perceiving and directing any variation deriving from the brain and from the environment (Pierpaoli, 1994).
In the course of my research in the last thirty years, I realized that all therapeutic trials aimed at treating highly invasive and metastatic cancer resulted into blatant flops, where the ‘prolonged survival’ obtained sometimes with the use of massive doses of ‘chemotherapic’ drugs, was in fact hiding horrendous and prolonged pains and agony and a condition of complete physical debilitation and psychic desperation.
The collapse of all defenses against the tumor without or after chemotherapy requires in fact an extreme intervention which may create ex-novo a condition in which the body acquires new means to recognize and to arrest, if not to destroy, invasive cancer. In my view, the only system to rapidly confer to the patient a novel capacity to react to an invasive and metastatic cancer is transplantation of bone marrow, obtained via total body irradiation of the patient’s marrow, followed by intravenous infusion of bone marrow from a genetically incompatible donor or from an animal (e.g. the pig).
Lengthy studies accomplished in the last 25 years (Pierpaoli et al., 1981, 1991; Deeg et al. 1996; Pierpaoli, et al., 1996a-c; led me to the conclusion that the present methods on which transplantation of bone marrow is based and performed in e.g. leukemias of various kind, are totally wrong. In fact, we can hope to cure all kind of leukemias, including highly resistant chronic myeloid leukemia and also localized, invasive or metastatic cancer, only by adopting the bone marrow from a donor genetically different from the recipient! In the case of malignant and invasive tumor, not even transplantation of bone marrow deriving from a healthy donor and incompatible with the recipient’s marrow will be able to achieve an inhibition of tumor growth and its rejection. My experiments with rodents show in fact that haemopoietic chimerism obtained by transplanting bone marrow between animals of the same species, even totally different from the immunogenetic point of view, cannot arrest growth of the tumor (Pierpaoli, 1985). It is evident that, in man, we must resort to transplantation of bone marrow from an animal of a different species, namely to xenotransplantation (Pierpaoli et al., 1996a-c).
I do not doubt that the new method we have developed needs urgent clinical testing. It will result into tumor rejection and, at the same time, from an immunological viewpoint, will avoid rejection of the grafted xenogeneic marrow by the recipient (host-versus graft reaction) and produce tolerance of the grafted marrow against his host (graft-versus-host reaction), resulting in rejection of the tumor and xenogeneic haemopoietic chimerism (Pierpaoli, 1998).
It is not feasible in fact that an immediate and bidirectional immunological tolerance be established between human tumor antigens and a heterologous (xenogeneic) immune system originating from a totally different species. Therefore our research points to xenogeneic bone marrow transplantation from pig to man with our innovative method based on the use of donor transferrins (Pierpaoli et al., 1996a-c; Pierpaoli, 1998). I do believe that this is the solution to the cure of metastatic invasive cancer and I do not doubt that this is the only possible therapy in the extreme cases in which any other therapy, as mentioned above, has failed. Only by conferring to the cancer bearer a new, radically different xenogeneic donor-type lympho-haemopoietic and immune system, we can be sure that the mechanisms of ‘immunological surveillance’ will be reactivated against the tumor. With this approach we can hope for a regression or even total disappearance of the tumor. We must accelerate the development of this new approach and bring it from the experimental to the clinical stage (Pierpaoli, 1998).
I wish here to remind us that the concept of polypeptide hormones being involved in carcinogenesis has been beautifully demonstrated long ago by Jacob Furth and a number of other investigators (Furth, 1955; Christakos et al., 1976; Nagasawa, 1979; Muehlbock and Boot, 1959; Burgess, 1985; Greenberg et al., 1984; Mittra and Hayward, 1974; Rao, 1972).
An experiment combining both concepts that A) a congenital or acquired hormonal alteration or a genetic defect of polypeptide hormones or ‘trophic factors’ synthesis and release is involved in oncogenesis (Hoag, 1963; Nagasawa, 1979; Welsch, 1985; Pierpaoli and Meshorer, 1982;, Dilman, 1986) and that B) the pineal gland controls the rhythmic synthesis and release of pituitary polypeptide hormones (Clark and Baker, 1964; Nordlund and Lenner, 1977; Morin et al., 1977) has been recently performed by using the well-known model of female C3H/He mice strain with high incidence of spontaneous mammary cancer (Sinha et al., 1974).
The idea underlying our experiment was that the genetically abnormal pineal gland of cancer-prone C3H female mice may be determinant for the congenital increased secretion of prolactin in their pituitary gland (Sinha et al., 1974), similarly to prevention of autoimmune diseases and cancer in NZB mice given nocturnal melatonin (Pierpaoli, 1991).
We have in fact succeeded in demonstrating that early removal of the pineal gland in such a strain of female mice totally prevents onset of cancer and prolongs their life (Bulian and Pierpaoli, 2000). These findings demonstrate beyond any doubt that induced, acquired or congenital, chronic alteration of hormone synthesis and release anticipates onset of tumors and is fundamental for the neuro-endocrine imbalance resulting into breakage of ‘immunological surveillance’ and onset of cancer (Bulian and Pierpaoli, 2000). In addition, they show that the pineal network, as I had suggested (Pierpaoli, 1991, 1994, Pierpaoli and Lesnikov, 1997), is the true “director” of the hormonal orchestra and controls those cyclic rhythms of hormone synthesis and release which is basic for controlling the ‘aging program’ (Pierpaoli and Regelson, 1994).
I conclude by suggesting a novel and simple approach for prevention and cure of cancer by early detection of quantitative and qualitative alterations of synthesis and release of hormones such as growth hormone, prolactin, TSH, gonadotropins, adrenal gonadal steroids and insulin. In particular, I recommend tracing abnormalities of prolactin and TSH, being their continuous and increased release highly carcinogenic (Furth, 1955; Speiser et al., 1966; Jull, 1973).
Being that ‘immunological surveillance’ against cancer is totally dependent on physiological hormonal cyclicity (Pierpaoli, 1994), and being that the pineal gland and its links to the entire brain circuits are responsible for the maintenance of perfect circadian hormonal rhythms (day-night, seasonal), the protection of the pineal gland from stress and aging with administration of nocturnal, exogenous melatonin is presently the best way to prevent cancer and to re-create the conditions for a rapid restoration of anti-cancer immunity in cancer-affected patients.
I heard somebody rightly saying: “Melatonin is not a cure for cancer, but you cannot cure cancer without melatonin!”