Already in the last century, a German biologist, Ernest Haeckele (1834-1919), departing from the Linnaeian concept that makes for two great kingdoms of living things (vegetable and animal) denounced the difficulties of categorising all those microscopic organisms which, because of their characteristics and properties, could not be attributed to either the vegetable or animal kingdom. For these organisms, he proposed a third kingdom, called Protists.
“This vast and complex world includes a range of entities beginning with those that have sub-cellular structure — existing at the limits of life — such as viroids and viruses, moving through the mycoplasms, to finally, organisms of greater organisation: bacteria, actinomycetes, mixomycetes, fungi, protozoa, and perhaps even some microscopic algae.” (2).
The common element of these organisms is the feeding system, which, being implemented (with very few exceptions) by direct absorption of soluble organic compounds, differentiates them both from animals and vegetables. Animals also feed as above, but especially by ingesting solid organic materials that are then transformed through the digestive process. Vegetables are capable, by utilising mineral compounds and light energy, to feed by synthesising the organic substances.
The contemporary tendency of biologists is to once again pick up, though in a more sophisticated way, the concept of the third kingdom. One goes even further, however, arguing that within that kingdom, fungi must be classified in a distinct category.
O. Verona (3) says that if we put multicellular organisms provided with photosynthetic capabilities (plants) in the first kingdom, and the organisms not provided with photosynthetic pigmentation (animals) in the second kingdom, and organisms from both these kingdoms are made of cells provided with a distinct nucleus (eukaryotes); and, furthermore, if we put in another kingdom (protists) those monocellular organisms that have no chlorophyll and have cells that are without a distinct nucleus (prokaryotes), the fungi can well have their own kingdom because of the absence of photosynthetic pigmentation, the ability to be mono-cellular, and multi-cellular, and, finally, their possession of a distinct nucleus.
Additionally, fungi possess a property that is strange when compared to all other micro-organisms: the ability to have a basic microscopic structure (hypha) with a simultaneous tendency to grow to remarkable dimensions (up to several kilograms), keeping unchanged the capacity to adapt and reproduce at any size.
From this point of view, therefore, fungi cannot be considered true organisms, but cellular aggregates sui generiswith an organismic behaviour, since each cell maintains its survival and reproductive potential intact regardless of the structure in which it exists.
It is therefore clear how difficult it is to identify all the biological processes in such complex living realities. In fact, even today, there are huge voids and taxonomical approximations in mycology.
It is worthwhile to examine more deeply this strange world, with such peculiar characteristics, and try to highlight those elements that somehow may be pertinent to the problems of oncology.
1) Fungi are heterotrophic organisms and therefore need, as far as nitrogen and carbon are concerned, pre-formed compounds. Of these compounds, simple carbohydrates, for example monosaccarides (glucose, fructose, and mannose) are among the most utilised sugars. This means that fungi, during their life cycle, depend on other living beings, which must be exploited in different degrees for their feeding. This occurs both in a saprophytic way (that is, by feeding on organic waste) and in a parasitic way (that is, by attacking the tissue of the host directly).
2) Fungi show a great variety of reproductive manifestations (sexual, asexual, gemmation; these manifestations can often be observed simultaneously in the same mycete), combined with a great morphostructural variety of organs. All of this is directed toward the end of spore formation, to which the continuity and propagation of the species is entrusted.
3) In mycology, it is often possible to observe a particular phenomenon called heterocarion, characterised by the coexistence of normal and mutant nuclei in cells that have undergone a hyphal fusion.
Nowadays, phitopathologists are quite worried about the creation of individuals that are genetically quite different even from the parents. This difference has taken place by means of those reproductive cycles, which are called parasexual.
The indiscriminate use of phitopharmaceuticals has in fact often determined mutations of the nuclei of many parasite fungi with the consequent creation of heterocarion — and this is sometimes particularly virulent in its pathogenicity (4).
4) In the parasitic dimension, fungi can develop from the hyphas more or less beak-shaped specialised structures that allow the penetration of the host.
5) The production of spores can be so abundant as to always include, at every cycle, tens, hundreds, and even thousands of millions of elements that can be dispersed at a remarkable distance from the point of origin (a small movement is sufficient, for example, to implement immediate diffusion).
6) Spores have an immense resistance to external aggression, for they are capable of staying dormant in adverse conditions for many years, while preserving unaltered their regenerative potentialities.
7) The development coefficient of the hyphal apexes after the germination is extremely fast (100 microns per minute under ideal conditions) with ramification capacity, thus with the appearance of a new apex region that in some cases is in the neighbourhood of 40-60 seconds (6).
8) The shape of the fungus is never defined, for it is imposed by the environment in which the fungus develops.
It is possible to observe, for example, the same mycelium in the simple isolated hyphas status in a liquid environment or in the form of aggregates that are increasingly solid and compact up to the formation of pseudoparenchymas and of filaments and mycelial strings (7).
9) By the same token, it is possible to observe in different fungi the same shape whenever they must adapt to the same environment (this is called dimorphism).
The partial or total substitution of nourishing substances induces frequent mutations in fungi, and this is further proof of their high adaptability to any sub-strata.
10) When the nutritional conditions are precarious, many fungi react with hyphal fusion (among nearby fungi) which allows them to explore the available material more easily, using more complete physiological processes.
This property, which substitutes co-operation for competition, makes them distinct from any other microorganism, and for this reason Buller calls them social organisms (8).
11) When a cell gets old or becomes damaged (i.e. by a toxic substance or by a pharmaceutical) many fungi whose intercellular septums are provided with a pore react by implementing of a defence process calledprotoplasmic flux through which they transfer the nucleus and cytoplasm of the damaged cell into a healthy one, thus conserving unaltered all their biological potential.
12) The phenomena regulating the development of hyphal ramification are unknown to date (9). They consist either of a rhythmic development, or in the appearance of sectors which, though they originate from the hyphal system, are self-regulating (10), that is, independent of the regulating action and behaviour of the rest of the colony.
13) Fungi are capable of implementing an infinite number of modifications to their own metabolism in order to overcome the defence mechanism of the host. These modifications are implemented through plasmatic and biochemical actions as well as by a volumetric increase (hypertrophy) and numerical hyperplasy of the cells that have been attacked (11).
14) Fungi are so aggressive as to attack not only plants, animal tissue, food supplies and other fungi, but even protozoa, amoebas and nematodes.
Fungi hunt nematodes, for example, with peculiar hyphal modifications that constitute real mycelial criss-cross, viscose, or ring traps that achieve the immobilisation of the worms, as a precursor their hyphal invasion.
In some cases, the aggressive power of fungi is so great as to allow it, with only a cellular ring made up of three units, to tighten in its grip, capture and kill its prey in a short time notwithstanding the prey’s desperate struggling.
From the short notations above, therefore, it seems fair to dedicate a greater attention to the world of fungi, especially considering the fact that biologists and microbiologists constantly highlight large deficiencies and voids in all their descriptions and interpretations of the fungi’s shape, physiology and reproduction.
So the fungus, which is the most powerful and the most organised micro-organism known, seems to be an extremely logical candidate as a cause of neoplastic proliferation. Imperfect Fungi (so called because of the lack of knowledge and understanding of their biological processes) deserve particular attention since their essential prerogative sits in their fermentative capacity.
The greatest disease of mankind may therefore hide within the small cluster of pathogenic fungi, and may be after all be located with just some simple deductions able to close the circle and providing the solution.
Considering that, among the human parasite species, the Dermatophytes and Sporotrichum demonstrate an excessively specific morbidity, and that experience shows that Actinomycetes, Toluropsis and Hystoplasma rarely enter the context of pathology, the Candid Albicans clearly emerges as the sole candidate for tumoral proliferation.
If we stop for a second and reflect on its characteristics, we can observe many analogies with neoplastic disease. The most evident are:
1) Ubiquitous attachment: no organ or tissue is spared
2) The constant absence of hyperpyrexia
3) Sporadic and indirect involvement of the differential tissues
4) Invasiveness that is almost exclusively of the focal type
5) Progressive debilitation
6) Refractivity to any type of treatment
7) Proliferation facilitated by multiplicity of indifferent cofounders
8) Symptomatological basic configuration with structure tending to the chronic
Therefore an exceptionally high and diversified pathogenic potentiality exists in this mycete of just a few microns in size, which, even though it cannot be traced with the present experimental instruments, cannot be neglected from the clinical point of view.
Certainly, its present nosological classification cannot be satisfactory, because if we do not keep the possibly endless parasitic configurations in mind, that classification is too simplistic and constraining.
We therefore have to hypothesise that Candida, in the moment it is attacked by the immunological system of the host or by a conventional antimycotic treatment, does not react in the usual, predicted way, but defends itself by transforming itself into ever-smaller and non-differentiated elements that maintain their fecundity intact to the point of hiding their presence both to the host organism and to possible diagnostic investigations.
The Candida’s behaviour may be considered to be almost elastic:
When favourable conditions exist, it thrives on an epithelium; as soon as the tissue reaction is engaged, it massively transforms itself into a form that is less productive but impervious to attack — the spore.
If then continuous sub-epithelial solutions take place coupled with a greater a-reactivity in that very moment the spore gets deeper in the lower connective tissue in such an impervious state, it is irreversible.
In fact, the Candida takes advantage of a structural interchangeability utilising, according to the difficulties to overcome its biological niche.
In this way, Candida is free to expand to maturation in the soil, air, water, vegetation, etc., that is, wherever there is no antibody reaction.
In the epithelium, instead, it takes a mixed form, that is reduced to the sole spore component when it penetrates in the lower epithelial levels, where it tends to expand again in the presence of conditions tissular a-reactivity.
The initial mandatory step of an in-depth research endeavour would be to understand if and in which dimensions the spore transcends; what mechanisms it engages to hide itself or, again, if it preserves its parasitical characteristic, or if it has available a neutral quiescent position, which is difficult or even impossible to detect by the immunological system.
Unfortunately today we do not have the appropriate means, either theoretical or technical, to answer these and similar questions, so that the only valid suggestions can come solely from clinical observation and experience. While not providing immediate solutions, these sources can at stimulate further questions.
Assuming that Candida Albicans is the agent responsible for tumoral development, a targeted therapy would keep into account not just its static and macroscopic manifestations, but even the ultramicroscopic ones especially in their dynamic valence, that is, the reproductive.
It is very probable that the targets to attack are the fungi’s dimensional transition points in order to perform a decontamination with such a scope as to include the whole spectrum of the biological expression: parasitic, vegetative, sporal, and even ultra-dimensional and, to the limit, viral.
If we stop at the most evident phenomena, we risk administering salves and unguents forever (in the case of dermatomycosis or in psoriasis), or to clumsily attack (with surgery, radiotherapy or chemotherapy) enigmatic tumoral masses with the sole result of facilitating their propagation, which is already heightened in the mycelial forms.
Why, one may ask, should we assume a different and heightened activity of Candida Albicans since it has been abundantly described in its pathological manifestations?
The answer lies in the fact that it has been studied only in a pathogenic context, that is, only in relation to the epithelial tissues. In reality Candida possesses an aggressive valence that is diversified in function of the target tissue. It is just in the connective or in the connective environment, in fact, and not in the differentiated tissues, that Candida may find conditions favourable to an unlimited expansion.
This emerges if we stop and reflect for a moment on the main function of connective tissue, which is to convey and supply nourishing substances to the cells of the whole organism.
This is to be considered as an environment external to the more differentiated cells such as nervous, muscular, etc. It is in this context, in fact, that the alimentary competition takes place.
On one hand we have the organism’s cellular elements trying to defeat all forms of invasion; on the other hand, we have fungal cells trying to absorb ever-growing quantities of nourishing substances, for they have to obey the species’ biological imperative to form ever-larger and diffused masses and colonies.
Candida can only exist as saprophyte Second Non-integer epitheliums (erosions, abrasions, etc.), absence of stage debilitating factors, unusual transitory conditions (acidosis, metabolic disorder, and microbial disorder). Candida expands superficially (classic mycosis, both exogenous and endogenous). Third Non-integer epitheliums, presence of debilitating factors (toxic, stage radiant, traumatic, neuropsychic, etc.).
Candida goes deeper into the sub-epithelial levels from which it can be carried to the whole organism through the blood and lymph (intimate mycosis). (12) Stages one and two are the most studied and known, while stage three, though it has been described in its morphological diversity, is reduced to a silent form of saprophytism.
This is not acceptable from a logical point of view, because no one can demonstrate the harmlessness of the fungal cells in the deepest parts of the organism. In fact, the assumption that Candida can behave in the same saprophytic manner that is observed on integer epitheliums when it has successfully penetrated the lower levels is at least risky, because the assumption would have to be sustained by concepts that aretotally aleatory.
In fact, we asked not only to accept a priori that the connective environment is (a) not suitable to nourish the Candida, but also at the same time to accept (b) the omnipotence of the body’s defence system towards an organic structure that is invasive but that then becomes vulnerable once lodged in the deeper tissues.
As to point a), it is difficult to imagine that a micro-organism so able to adapt itself to any sub-strata cannot find elements to support itself in the human organic substance; by the same token, it seems risky to hypothesise that the human organism’s defence system is totally efficient at every moment of its existence.
Finally, the assumption that there is a tendency to a state of quiescence and vulnerability in the case of a pathogenic agent such as fungus — the most invasive and aggressive microorganism existing in nature — seems to carry a whiff of irresponsible.
It is therefore urgent, on the basis of the above-mentioned considerations, to recognise the hazardous nature of such a pathogenic agent, which is capable of easily taking the most various biological configurations, both biochemical and structural, in function of the condition of the host organism.
The fungal expansion gradient in fact becomes steeper as the tissue that is the host of the mycotic invasion becomes less eutrophic, and thus less reactive.
To that end, it seems useful to briefly consider the “benign tumour” nosological entity. This is an issue that always appears in general pathology but that indeed is brushed aside most of the time too easily, and it is overlooked, since it usually doesn’t create either problems or worries. It constitutes one of those underestimated grey areas seldom subjected to rational, fresh consideration.
If the benign tumour, however, is not considered a full-fledged tumour, it would be advantageous, for clarity, to categorise it in an appropriate nosological scheme. If, instead, it is thought that it fully belongs to neoplastic pathology, then it is necessary to consider its non-invasive character and consequently to consider the reasons for this.
It is in fact evident how in this second scenario, the thesis based on a presumed predisposition of the organism to auto-phagocytosis, having to admit an expressive graduation, would stumble into such additional difficulties such as to become extremely improbable.
By contrast, in the fungal scenario, the mystery of why there are benign and malignant tumours is exhaustively solved, since they can be recognised as having same etiological genesis.
The benignity or malignancy of a cancer in fact depends on the capability of tissular reaction of a specific organ expressing itself ultimately in the ability to encyst fungal cells, and to prevent them from developing in ever-larger colonies. This can be achieved more easily where the ratio between differentiated cells and connective tissue is in favour of the former.
Situated between the impervious noble tissues, then, and the defenceless connective, the differentiated connective structures (the glandular structures in particular) represent that medium term which is only somewhat vulnerable to attack, because of an ability to offer a certain type of defence.
And it is in these conditions that benign tumours are formed, that is, where the glandular connective tissue is successful in forming hypertrophic and hyperplastic cellular embankments against the parasites.
In the stomach and in the lung, instead, since there are no specific glandular units, the target organ, provided with a small defensive capability, is at the mercy of the invader. Furthermore, it is worth mentioning how several types of intimate fungal invasion do not determine the appearance of malignant or benign tumours, but a type of particular benign tumour (specific degenerative alterations) as is the case of some organs or apparatuses that do not have peculiar glandular structures, but nevertheless are attacked in their connective tissue, but in a limited way.
If we consider, in fact, multiple sclerosis, SLA, psoriasis, nodular panartherite, etc. the possible development of the fungus in a three-dimensional sense is actually limited by the anatomic configuration of the invaded tissues, so that only a longitudinal expansion is allowed.
Going back to the precondition of a-reactivity that is necessary for neoplastic development in a specific individual, it is permissible to affirm how in the human body each external or internal element that determines a reduction of well-being in an organism, organ or tissue, possesses oncogenic potentiality. This is not so much because of an intrinsic damaging capability as much as for a generic property of favouring the fungal (that is, tumoral) flourishing.
Then the causal network so much invoked in contemporary oncology, which involves toxic, genetic, immunological, psychological, geographical, moral, social, and other factors, finds a correct classification only in a mycotic infectious perspective where the arithmetical and diachronic summation of harmful elements works as a cofactor to the external aggression.
Having theoretically demonstrated the equivalency tumour = fungus, it is clear how this interpretative key offers a long series of questions concerning the contemporary therapies both oncological (used without reference indexes) and antimycotic (utilised only at a superficial level).
Which path is best to walk today, then, when faced with a cancer patient, since the conventional oncological treatment, not being etiological, can only occasionally have positive effects and most of the time produces damage?
In the fungal perspective in fact, the effectiveness of surgery is noticeably reduced because of the extreme diffusibility and invasiveness characteristic of a mycelial conglomerate. Surgery’s to solve the problem is therefore tied to the case — to conditions, that is, in which one has the luck to completely remove the entire colony (which is often possible in the presence of a sufficient encystment; but here we are in the case of benign tumours).
Chemotherapy and radiotherapy produce almost exclusively negative effects, both for their specific ineffectiveness, and for their high toxicity and harmfulness to the tissues, which in the last analysis favours mycotic aggressiveness.
By contrast, an anti-fungal, anti-tumour specific therapy would keep into account the importance of the connective tissue, together with the reproductive complexity of fungi. Only by attacking the fungi across the spectrum of all its forms, at points where it is most vulnerable from the nutritional point of view, would it be possible to hope to eradicate them from the human organism.
The first step to take, therefore, would be to reinforce the cancer patient with generic reconstituent measures (nutrition, tonics, regulation of rhythms and vital functions), that are able to enhance, by themselves, the general defences of the organism.
Concerning the possibility of having available pharmaceutical cures which unfortunately do not exist today, it seems useful, in the attempt to find an anti-fungal substance that is quite diffusible and therefore effective, to consider the extreme sensitivity of Candida towards sodium bicarbonate (i.e. in the oral candidosis of breasted babies). This is consistent with the fact that Candida has an accentuated ability to reproduce in an acid environment.
Theoretically, therefore, if treatments that put the fungus in direct contact with high bicarbonate concentrations could be found, we should be able to see a regression of the tumoral masses.
And this is what happens in many types of tumour, such as colon, liver — and especially stomach and lung — the former susceptible to regression just because of its “external” anatomic position, the latter because of the high diffusibility of sodium bicarbonate in the bronchial system and for its high responsiveness to general reconstituent measures.
By applying a similar therapeutic approach, it has been possible in some patients (about 30 in the last 15 years) to achieve complete remission of the symptomatology and normalisation of the instrumental data.