G. Zajicek

Cancer as a systemic disease

Theories on the nature of cancer may be classified into two categories. One regards cancer strictly as a local phenomenon while the second looks at cancer as a local manifestation of a systemic process or disease. Although the first dominates current medical thought, the theories of immunological surveillance and of protovirus-oncogene implicitly assume cancer to represent a local manifestation of a systemic process or disease. This is supported also by epidemiological data forwarded in the present paper. In order to clarify the exact meaning of a systemic disease, cancer and its manifestation are compared with arteriosclerosis and its sequelae. Arteriosclerosis could be regarded as a prototype of a systemic disease. It presents itself clinically solely by its local manifestations, like myocardial infarction or stroke. These local manifestations may be followed by secondary systemic sequelae like congestive heart failure. In the same context, it is proposed to regard cancer as one systemic disease which presents itself clinically by local phenomena like carcinoma, lymphoma and sarcoma. These local manifestations may lead further to secondary systemic sequelae like metastasis.

Metastasis as a beneficial process

The most important message to be found in the Fourth report on end results in cancer in the U.S., states that with the progression of cancer, its force of mortality declines. This has been reexamined in the present study. The declining force of mortality implies that as the disease advances the chances of the average patient to survive, improve. Since in the cancer patient all vital functions gradually deteriorate, and the only process gaining with time is his tumor load, one has to consider the possibility that the improving chances of the cancer patient could be linked with the amount of tumor mass in his body. These ideas are illustrated by the following example. Cancer could result from a gradual loss of a vital tissue product A, to be replaced by an analogous tissue product B which is of embryonal origin. In the adult, B is produced by stem cells which gradually adapt to the loss of the primary product and increase in number. B is less efficient than A to meet the necessary vital functions. Its deficiency in quality is however augmented by quantity. In order to keep up with the increasing demand, the stem cells proliferate and spread throughout the organism where each metastasis continues to secrete B. The penalty inflicted by this compensatory mechanism is relatively high. Some metastases hit vital functions, and the increasing tumor load depletes the available energy sources. The net effect however is beneficial since without metastasis the organism would have succumbed to the disease in its earliest stage.

Proliferon: the functional unit of rapidly proliferating organs.

Continuously replicating organs are generally composed of several cell population types. These may be divided according to their function into two classes: 1. parenchyma: cells destined to perform a certain metabolic function peculiar to the organ under study, 2. supporting cell populations, consisting of fibroblasts and vascular supply always accompanied by nerve fibers. The kinetics of all the cells are highly coordinated. They all share one progenitor region. It is postulated that in this common progenitor region the two cell population classes are assembled into complex units denominated as proliferons. The proliferon starts its existence as a whole, matures as a whole and disintegrates at the organ periphery. It consists of four basic elements: parenchyma, connective tissue, blood vessels and nerve fibers. This model has been previously called upon to describe the kinetics of the rodent incisor tooth and the intestinal mucosa. It is assumed to be the elementary functional unit of all rapidly proliferating organs such as: skin, hair, endometrium, bone marrow, intestinal mucosa and rodent incisor.

The risk of cancer therapy

Survival times of treated cancer patients are distributed lognormally. This density function exhibits a peak accompanied by a long tail which asymptotically approaches the abscissa. The lognormal conditional failure rate, known also as force of mortality, which describes the chances of a patient remaining alive, initially climbs, to decline at a later phase. This decline is observable in all survival curves of the Fourth report on the end results of cancer in the U.S., and has been documented also by other epidemiological surveys. It implies that with the progression of the disease the chances of the average patient to survive improve. This pattern indicates the existence of a mechanism which is assumed to be associated with neoplasia, and assists the patient to withstand cancer. The initial rise of the force of mortality is assumed here to be associated with cancer treatment which undermines the beneficial role of neoplasia.

The ideal human neoplasm

Abstract Clinical cancer manifestations are divided into three categories: 1. Primary cancer manifestations e.g. cachexia. 2. Neoplasia, which is generally regarded as a local phenomenon and 3. Secondary systemic sequelae of neoplasia, e.g. functional loss due to metastatic involvement. The theory coined as the “Ideal Human Neoplasm” (IHN) outlines the salient features of neoplastic progression and provides a framework in which this change may be expressed precisely and rigorously. Neoplasia is manifested by three elementary biological phenomena: Proliferation, differentiation and morphogenesis. Neoplasms are classified according to their replicative tissue group origin into two major groups: Type I, which rise from rapidly replicating organs such as bone marrow, gastro intestinal mucosa and endometrium and type II neoplasms, originating in slowly proliferating organs e.g. liver and kidney. The theory deals solely with adult type I neoplasms. It provides laws common to all type I neoplasms and outlines a common developmental pathway shared by all of them. Neoplasia is regarded as organ manifestation, a notion which disagrees with the commonly accepted one which regards neoplasia solely as a tissue manifestation. Colon carcinoma for instance is viewed here as an aberration of the whole mucosa and not only of its epithelial tissue. Carcinogenesis is marked by two processes proceeding hand in hand. A gradual and continuous expansion of progenitor cells accompanied by their dedifferentiation. IHN forms a part of a more generalized theory which views neoplasia as a protective mechanism mobilized by the organism to withstand the gradual systemic deterioration of cancer, e.g. cachexia.

Resistance to cancer chemotherapy

Human cancers are either refractory to chemotherapy, or acquire resistance to it. Although acquired resistance to chemotherapy is generally ascribed to the drug itself, it may be linked with the nature of neoplasia, since normal tissues e.g. gastrointestinal mucosa or bone marrow, do not seem to acquire resistance and their perpetuating sensitivity even undermines effective treatment. According to the theory presented herewith, chemotherapy ultimately fails since it is based on wrong premises. Cancer is regarded here as a metabolic deficiency, originating in stem cell destruction. Besides serving as tissue progenitors, stem cells are postulated to secrete a vital substance A necessary for proper tissue function. Carcinogens interfere with A production mainly by destroying stem cells, which the organism is incapable of fully replenishing, so that less A is produced. This irreversible A deficiency may be replenished solely by a substitute, or substance B, produced by a specialized organ, the neoplasm. Since carcinogens continue depleting additional stem cells, the deficiency worsens. In order to keep up with increasing demand the neoplasm has to proliferate more and more until it reaches a stage of decompensation when the harm inflicted by it outweighs its benefit. Stem cell depletion is regarded here as the common final pathway of carcinogens. The theory predicts that following a supply of A producing stem cells or inactivated B producing neoplastic stem cells, the tumor will regress. Tumor regression is achievable also by diminishing the demand for the missing metabolites, which may be accomplished by chemotherapy. A and B are consumed mainly by transitional cells. Upon their elimination the demand for A declines and the tumor may wane. This is regarded here as the main role of chemotherapy in cancer, while its tumoricidal potency is indicated solely for repairing tumor induced function loss. It is proposed here that the good response to chemotherapy by Hodgkins disease and seminoma is linked with their being partially infective. Both start as genuine smouldering infections turning later into neoplasms. While chemotherapy is adequate only during the infective phase, it is met with mounting resistance when applied during the neoplastic phase.

Inflammation initiates cancer by depleting stem cells

According to the theory presented herewith, neoplasia results solely from stem cell depletion. Besides serving as tissue progenitors, stem cells are postulated to secrete a vital substance A necessary for proper tissue function. Carcinogens interfere with A production mainly by destroying stem cells and since the latter are not replenished, less A is produced. In order to repair the deficiency, the organism grows a special organ, the neoplasm, dedicated to produce a substitute, denominated here as substance B. Since carcinogens continue depleting stem cells, the neoplasm has to grow more and more in order to keep up with the demand, until reaching a stage of decompensation when the harm inflicted by it is greater than its benefit. Any stem cell depleting substance or process e.g. ablation, chemotherapy and inflammation, is regarded here as a carcinogen. Even animal tumor viruses are postulated here to exert their harm mainly by depleting stem cells. Protracted inflammation e.g. ulcerative colitis or cystic mastopathy, hits stem cells and is followed therefore by neoplasia. Age specific incidence rates of such pathologies resemble precursor-successor curves of tracer kinetics. The precursor inflammation hits young adults, while its successive neoplasia is more prevalent in older individuals. Although most age specific curves of adult cancers are unimodal, at least five are bimodal, resembling precursor-successor curves. These are: Hodgkins disease, seminoma, nasopharyngeal and retroperitoneal tumors and cancer of bone and joints. It is suggested here that these age specific curves are mixtures of two pathologies, an inflammatory, which is prevalent in young persons, followed by neoplasia.

Neoplasia — A stem cell pathology

Cell proliferation in the organism is accompanied by cell displacement. Proliferating tissues exhibit three key characteristics: a site of origin of the stem cell, a tissue radius along which all constituents except the stem cell are displaced and a periphery where cells are eliminated. The tissue thus consists of two cell types: Stem and transitional. Since only the first resides permanently in the tissue any lasting change observed in the tissue is directed by the stem cell. Each stem cell division results in two cell types: one replacing the parent cell to remain a stem cell, while the other originates an outward displaced transitional cell clone whose life span is limited. In the normal state, the stem cell pool is constant, although its replenishment capacity is limited. Neoplasia is regarded here as a purposeful tissue alteration originating in a stem cell change manifested by: Aneuploidy, maturation arrest, stem cell pool enlargement and increasing cell turnover. Stem cells are assumed to secrete a substance A necessary for a proper tissue function, whose production is impeded by carcinogens, mainly by stem cell depletion. Since however stem cell replenishment is limited, the organism grows a specialized organ, the neoplasm, producing a less efficient substitute for A, denominated here as substance B. Neoplastic growth is indirectly dependent upon the abundance of substance A, the supply of which should be followed by a reduction of neoplastic mass. Neoplasia is thus viewed here as a protective function directed by the stem cell and linked with oncogenes. Each determined stem cell is harbouring a specific oncogene and exhibits a typical neoplasm. Since the theory predicts that neoplastic growth indirectly depends upon the abundance of substance A, it may be tested by investigating the effect of substance A producing stem cells upon the growing neoplasm. Their supply to the organism should be followed by a reduction of the neoplastic mass.

The histogenesis of glandular neoplasia

Tissues in the organism may be divided according to their proliferative capacities into three categories: 1. Fast replicators (FR) e.g., epidermis; 2. Slow replicators (SR) e.g., liver and 3. Non replicators (NR) e.g., nerve cells. Evidence is presented that FR as well as SR tissues continuously proliferate exhibiting two distinct histomorphological structures; a progenitor region in which cells are formed and a functional region into which they enter. Throughout their displacement, the cells cover a typical path denominated as tissue radius. The SR tissues e.g., parotid gland, mammary gland, liver and prostate, exhibit similar ontogenies, and proceed during regeneration and neoplasia through similar stages. All are compound glands with two distinct stem cell types, one residing in the excretory duct epithelium and the second in the intercalated duct. Each stem cell gives rise to its typical neoplasm. Excretory duct originating neoplasms consist of papillomas, epidermal and adenocarcinomas, while intercalated stem cell bound neoplasms embrace the canalicular adenoma, oncocytoma acinic cell and lobular carcinomata. All tissues continuously stream along the tissue radius. Evidence is presented that even the liver cords are continuously displaced from the limiting lamina toward the terminal hepatic (or central) vein. The histological image of these tissues actually reflects an instantaneous picture of cells in a continuous flux.

On neoplastic grading

Abstract An adequate neoplastic grading system should provide a framework for a precise expression of cell turnover and differentiation. The grading system proposed herewith is applicable to all tissue pathologies associated with changes in cell turnover and differentiation, including neoplasia. It is illustrated on rapidly proliferating tissues known as continuous replicators e.g. the colon crypt epithelium. The enterocyte starts its existence at crypt bottom, during a stem cell division whereupon it gradually advances outward, differentiating as it goes. The typical path covered by the cell, denominated as tissue radius summarizes its life history. The cell is viewed as a point advancing on the radius in a rectlinear motion, defined by two variables: Distance from radius origin ‘x’, defined as the cell location number separating it from origin, and its velocity v(x) defined as the cell location number it covers per unit of time. The path the cell covers is represented by a trajectory in a two dimensional Galilean geometry. The cells transition from state to state is defined by two transformations: Displacement and shear. Each continuous replicator is represented by a typical trajectory which differs in different pathologies. Neoplastic progression in the continuous replicator may be expressed as a trajectory in the Galilean geometry, which serves also for a unique grading of neoplasia.