1  Failure of the current dogma    

            Many share an uneasy feeling that something is fundamentally wrong in our interpretation of cancer. Our ignorance is generally attributed to insufficient information that is necessary to comprehend cancer correctly  and since patients have to be treated anyhow, treatment is obviously inadequate. Such an attitude however is not unique to cancer. It constitutes the central motto of medicine: "To treat despite uncertainty", and yet it seems as if in cancer these doubts are more pronounced than in any other chronic disease. 

            Obviously we still do not understand cancer. On the other hand,  do we understand arteriosclerosis better? It kills more patients than cancer  and yet even if treatment has failed we are satisfied that the patient was treated properly. Such a sense of self-confidence is not shared by  the oncologist. In spite of being armed with the most sophisticated means known in medicine, he helplessly follows the patient into his grave. Take for instance the guiding principle of cancer treatment, according to which cancer is a parasite originating in a chance event, transforming a healthy cell into a fierce crab, proliferating without restraint until destroying its host . This parasite should obviously be eliminated as soon as possible. And yet  despite its simplicity, this guiding principle fails to cure most patients.   
       
             Twenty years after "launching the war" on cancer, leading specialists admitted that the war is being lost (1-3). The National Cancer Institute (NCI) has spent more than $1 billion on breast cancer alone and yet breast cancer mortality does not change. Despite intensive effort to eradicate the parasite upon its detection,  from 1930 till 1988, age adjusted mortality  of breast cancer has remained virtually constant (4,5). Fifty eight years of continuous debates about the preferred treatment of breast cancer failed to improve the patient's life prospect. Failure is attributed to micro-metastases that have spread prior to tumor detection, yet patients with breast cancer may carry micro-metastases for years without any clinical manifestations (6).   

            Treatment failed since it is based on false premises. It reflects  a failure of medical reasoning that seems adequate for all diseases except cancer. It is presumed here  that the necessary information for understanding  cancer exists and is wrongly interpreted.

            The present discourse introduces a new cancer paradigm according to which  cancer is a metabolic deficiency that ends in cachexia. The main task of neoplasia is to aleviate the deficiency and  prevent cachexia. 
           
2  Cancer starts as a systemic illness     
         
            There is more to cancer than just the crab. Two hallmarks of cancer,  cachexia, and para-neoplasia, are usually ignored  since it is assumed that they are caused by neoplasia (8). In some cases it appears as if cachexia and para-neoplasia accompany the tumor, yet usually  weight loss does not correlate with the type of cancer and  its  duration, nor with the site or number of metastases (9). Weight loss is  one of the earliest manifestations of malignancy (10), and cachexia can appear in patients with tumors that are less than 0.01% of the total body weight. (11) Also para-neoplasia is unrelated to tumor size, location, or the degree of metastasis, and may  antedate the discovery of the tumor by weeks , months, or even years (12).  In spite of this, oncology maintains that  neoplasia is the primary factor in cancer, and systemic effects are secondary. But, what if it is the other way around, and  cancer is first of all  a cachexia  accompanied by neoplasia? At least this could explain why in   most cancers treatment fails.  

            Above all, modern oncology maintains that  host is defenseless against its tumor and has to be screened and monitored otherwise he is doomed to die. This  conceptual impasse  is highlighted by a title of a recent book on cancer: "Contrary to Nature" (13). For centuries physicians were trained  to regard nature as their ally. The maxim "while Medicine heals, only Nature cures" was unfortunately abandoned by modern medicine. One has only to consider the profound complexity of  the human organism in order to realize that the  most one may hope to achieve, is to  assist the organism  in helping itself. Such a modesty toward the organism that guided our forefathers was abandoned by modern medicine, which  should be regarded as  root of the oncological failure. If cancer appears as contrary to nature it is wrongly comprehended and has to be reinterpreted so as to remain in accord with nature.

3  The example of pernicious anemia    

            Cancer is a disease of vertebrates induced by carcinogens that initiate  a metabolic deficiency  manifested by  para-neoplasia and cachexia. Neoplasia is regarded here as a protective strategy mobilized by the organism to repair a metabolic deficiency. During the  pre-clinical phase of cancer,  deficiency  is slight and compensated even by a minute tumor. With time it  gets worse and the tumor has to grow more and more in order to make up for the loss, causing pain and secondary damage to vital functions.  The patient  seeks help and  the disease starts  its clinical course (14). When the deficiency becomes  pronounced,  patient dies in a state of decompensation, known as crisis or relapse.   

            There is a disease called pernicious anemia  that illustrates how neoplasia might be protective. It is triggered by a "carcinogen" preventing the entry of vitamin B12 into the body. During its  pre-clinical phase, that lasts about two years, the patient is healthy. The clinical phase  starts with  anemia and "para-neoplasia", known   as combined  degeneration of the spinal cord and brain. The bone marrow displays "neoplastic" features, e.g., hyperplasia, maturation arrest,  and ineffective erythropiesis, that were  regarded in the past as "pseudo-leukemia" (15). These are  protective strategies of the bone marrow that keep the patient alive. With time the  deficiency  deepens more and more until reaching the state of decompensation whereupon the patient dies .

            Cancer is viewed here as pernicious cachexia induced by the loss of a vital metabolite that is secreted by stem cells and compensated by neoplasia.                       

4  Streaming organism

            The organism is  composed of myriads of cell streams that maintain homeo-rhesis. Each  stream represents one  tissue unit that is nourished by a determined stem cell (DS). All  cells   except  stem cell are transitional and their life span limited. Only the stem cell pool exists as long as the organism does.  

                    

5 Unit hypertrophy and hyperplasia

            Tissue units may enlarge by accumulating transitional cells, and when losing them they shrink. The two conditions are called respectively  hypertrophy and atrophy (or hypotrophy).  Unit hyperplasia occurs when entire units multiply, e.g., during growth. Bowel mucosa of the growing child elongates by forming new crypt units. First the determined stem cell in the mother crypt divides symmetrically, and generates an additional  determined stem cell that  forms a crypt bud. The bud elongates and finally  forms a new crypt. Each new unit adds one cell to the pool of determined stem cells. During hypoplasia, stem cells die and units disappear.          

6  The adult organism is incapable of  increasing its stem cell pool. 


            In the adult hardly any new units are formed, and when destroyed they are replenished  extremely slowly. Following small bowel resection, the remaining crypt-villus units become hypertrophic while hardly any new units are formed. Unit hypertrophy is the main compensatory mechanism of the adult in case of unit loss.  On the other hand, the growing child is capable of replenishing lost units by new ones.                 

7  Cancer starts by stem cell depletion

            The proposed metabolic deficiency of cancer starts with  stem cell depletion. Any agent that destroys stem cells is a carcinogen. Stem cell depletion triggers neoplasia in the same way as necrosis invokes  inflammation. Stem cells secrete a substance 'A' that is essential for the maintenance of transitional cells. When in the adult, stem cells are lost there ensues a deficiency of substance 'A'. Since  stem cell replenishment is sluggish, the organism activates a salvation strategy in form of the neoplasm for replenishing the loss.  The neoplasm secretes a substitute, called 'B', and restores the reversible deficiency.   During the  pre-clinical phase of cancer the deficiency  is slight and compensated even by a minute tumor. With time it  gets worse and in order to make up for the loss the tumor has to grow more and more, causing pain and secondary damage to vital functions.  The patient  seeks help and  the illness starts  its clinical course. When t deficiency becomes  pronounced,  the patient dies in a state of de-compensation, known as crisis or relapse.         

Neoplasia is a life saving process yet in an advanced stage it may cause damage , exactly as inflammation, also a life saving process that may also cause secondary damage. While inflammation repairs tissue damage, neoplasia repairs stem cell deficiency. When cancer advances, secondary damage by tumor predominates, which gave cancer with its crab metaphor        

8 Deficiency promotion      

            Two factors determine the  intensity of the 'A'  deficiency, Stem cell depletion by carcinogens, and its uptake rate by  transitional cells.  Agents that increase  'A' uptake by transitional cells are called promoters. Hormonal imbalance is a powerful deficiency promoter. It was demonstrated in a classical experiment in which ovarian tissue was transplanted into the spleen of castrated mice (23). Usually the secretion of pituitary gonadotrophins is modulated by steroid hormones that are secreted by the ovary. When transplanting the ovary into the spleen, steroids are metabolized by the liver and do not reach the pituitary. In the absence of hormonal feedback more and more gonadotrophins are secreted stimulating the transplanted tissue to proliferate until turning malignant. Since hormones do not deplete stem cells they are not carcinogenic. On the other hand, hormone overproduction  increases the pool of transitional cells that utilize more  of the stem cell product,  promoting a deficiency, that is later compensated by ovarian neoplasia.

9  Anti-promotion   
           
            Processes operating in cancer are balanced and reversible. For each process there exists an anti-process operating in the opposite direction. Any agent the diminishes the consumption of the stem cell metabolite by transitional  cells  is an anti-promoter. Anti-promotion is applied in the treatment of patients with disseminated breast cancer. Previously they were castrated and their adrenals  removed. Today the same  is achieved with hormonal analogues and irradiation.  These  procedures reduce the pool of transitional cells in the breast glands. The cells consume less of 'A' and its 'B' substitute, the deficiency declines,  the demand on the neoplasm diminishes, and it shrinks. By reducing the transitional cell pool, these measures act as anti-promoters.   

  
10  The main benefit of chemotherapy is its anti-promotion.  

            Chemotherapy is carcinogenic, since depleting  normal and  neoplastic stem cells. It is also an anti-promoter, since eliminating proliferating transitional   cells.  The outcome  of chemotherapy treatment depends on its effect on  each feature. Proliferating target cells are the most sensitive to chemotherapy, then come tissue stem cells and the least sensitive are neoplastic stem cells. When the patient is first treated,  chemotherpy reduces its proliferating transitional  cells (anti-promotion) and the deficiency is ameliorated.  Yet since chemotherapy depletes also stem cells and reduces the tumor, the relief is brief, the deficiency deepens and  the neoplasm  enlarges.   Since tumor stem cells are most resistant to chemotherapy, this therapy  is more harmful to 'A' secreting stem cells than to the tumor, and the illness becomes resistant to chemotherapy.     
           
            Anti-promotion  seems to be  also the main benefit of adjuvant chemotherapy in breast cancer. The drug poisons  first  the ovary and pituitary, reducing their hormonal output,  the breast tissue shrinks,  the deficiency declines and the neoplasm shrinks. The relative sizes of the two cell pools, stem and transitional, determine the state of the metabolic deficiency in cancer.

11 Anti-carcinogenesis       

            Any agent that increases the stem cell pool is anti-carcinogenic, e.g., unit hyperplasia  during organ growth. The child, unlike the adult,  can restore its deficiency by forming new 'A' producing stem cells. Childhood cancers are therefore  more benign than adult cancers and respond better to therapy. Most childhood cancers are actually congenital malformations induced by teratogens.  Generally teratogens  cause malformations yet when depleting also stem cells  malformations are accompanied also  by cancer.                              

12  Congenital neoplasia   

            Congenital tumors generally present themselves as poorly differentiated cell masses, growing more rapidly than most adult tissues do, and yet many regress spontaneously (24). Of the 29 cases of spontaneously regressing neuroblastomas documented by Everson and Cole (25), 21 were detected in infants under 6 months of age. The younger a child with a neoplasm the better its chances to be cured  since its anti-carcinogenic potential is the greatest. The estimated cure rate of neuroblastomas among neonates is about 62-70%, while after the age of two, only 5% are curable (26). This "oncogenic period of grace beginning in utero and extending through the first months of life" (27), reflects the anti-carcinogenicity of normal growth.   

13  Trophic  effect of neurons        

            The incompetence of the adult to replenish his missing stem cells is puzzling. Particularly since  the same stem cells when grown in vitro proliferate vigorously and may even  become immortal. Stem cell proliferation is restrained by  the nervous system.
           
            The nervous system is best known as  action potential carrier. Yet neurons participate also  in  the metabolism of their target organs. This function is known  as trophic effect of the neuron (28) and was first demonstrated in the regenerating newt limb (29). Following  limb amputation the stump is invaded by undifferentiated pluri-potential stem cells called blastema that gradually differentiate into a new limb.  This process depends upon  nerve supply. It  fails if  local nerves were removed. On the other hand if the local nerve supply was left intact and and the contra-lateral nerve trunk sutured  into the blastema region, the limb regenerates faster.          

            Similar trophic effects modulate the metabolism of muscles, or control the differentiation of taste buds (28). Apparently  the nervous system modulates the metabolism of all organs in the body as well as their stem cells and restrains them  from forming new tissue units. This trophic effect is poisoned by carcinogens that initiate the postulated 'A' deficiency and cancer.          


14  Cancer as neural disease         

            It is proposed that  stem cells are depleted also by a carcinogen induced neuropathy.  This possibility was raised under different circumstances by Janet McCredie who studied thalidomide induced phocomelia (30, 31). McCredie postulated that differentiation in the embryo is under neurotrophic control. Thalidomide induces a neuropathy and neuron death that is manifested later by malformations.  The same trophic relationship operates also in cancer. Para-neoplasia is an extended neuropathy that ends in cachexia and  is compensated by neoplasia.  

15  Cancer treatment          

            Carcinogen prevention is the best cancer treatment. When deficiency ensues it should be treated by replacement of the missing 'A' substance or its 'B' substitute. Since each tissue grows a different  neoplasm each cancer ought to be treated by the appropriate stem cells. Potential stem cell  sources are  animals or  humans whose stem cells can be enriched in vitro.                     

            Until the missing substance has been isolated, treatment should be directed to maintain neoplasia and correct its secondary manifestations. When secondary sequelae dominate the clinical picture, they have to be treated  even if it damages the stem cell pool  As deficiency progresses, one has to turn to  anti-promotion measures, e.g., endocrine ablation, or chemotherapy. Chemotherapy has to be applied sparingly,  and its dose  titrated in the same way as done during digitalization, raise it until  mild poisoning has been achieved, and not more.  

            It may seem strange that even cachexia contributes to the patient's well being. In spite his poor condition the patient maintains a delicate balance with his illness and his state proceeds an optimal course under the given circumstances. Cachexia is manifested by the depletion of transitional cells and acts therefore as anti-promoter.                        


16  Carcinogenesis by  organ resection.   

            Organ ablation is a carcinogen. Several studies have demonstrated that organ resection is followed  by an increased tendency to contract cancer in the treated organ. In one study,  6.5% percent of patients that had gastric surgery for benign conditions returned after five years with gastric stump carcinoma (41). A significantly increased mortality was detected also in  a cohort of patients that had partial gastrectomy for benign conditions (42). Partial colon resection promotes cancer growth in rats (43). Sprague-Dawley rats were treated with dimethylhydrazine for three months. After a treatment free period of five months, their colons were resected with an end-to-end anastomosis. One year after discontinuation of the carcinogen, and seven months after surgery, 50% had anastomotic tumors .
           
            Partial hepatectomy  accelerates hepato-carcinogenesis (44) by reducing the stem cell pool,  since the regenerating liver does not produce new units and compensates for the loss by unit hypertrophy.            

17  Inflammatory cancers   

            While in some esoteric cancers, e.g., Hodgkin's disease, seminoma, osteosarcoma, childhood leukemia, yield to massive irradiation or chemotherapy,  the overwhelming majority of cancers does not respond to this kind of treatment since adult cancers become resistant to chemotherapy. Resistance to chemotherapy is a hallmark of cancer and main reason for treatment failure. This feature may be regarded as a pathognomonic of  cancer so that  if a tumor yields to chemotherapy it is non cancerous.              

18  Hodgkin's disease         

            Hodgkin's disease, is the only cancer that called a disease, indicating that it behaves in a different way than genuine cancers.  Some authors suspect that it starts as granulomatous inflammation ending as lymphoma, being predominantly  granulomatous in young adults while in patients over 50 years, it is a lymphoma (45). Its age specific mortality curve exhibits a distinct a shoulder that accounts for  a  population of young adults with  the so called "benign" Hodgkin's  disease generally localized and). From the age of 50 year the curve ascends nearly exponentially and  could represent patients with  genuine lymphoma with features of malignant lymphosarcoma. In 284 patients with Hodgkin's disease, Reed-Sternberg cells, eosinophils and the extent of fibrosis were more pronounced in young adults, while atypical mitoses and other features of malignancy were more common in older persons (46). The authors were struck also by the epidemiological similarity between Hodgkin's disease and multiple sclerosis, suggesting that both could result from a very prevalent infection of low pathogenicity which is characteristic also of poliomyelitis (47).       

19  Seminoma          

            In seminoma the first peak is even more pronounced. Most seminomas exhibit a clear  inflammatory component, e.g., lymphocytic infiltration and granulomatous reaction (48). It appears as if seminoma, Hodgkin's disease, osteosarcoma and connective tissue sarcomas, start as  inflammatory diseases and only later turn into malignancies. Apparently total lymphoid irradiation and chemotherapy are effective only in their  infective phase  and less in their neoplastic stage exactly as  in non-Hodgkin lymphomas.  These neoplasms are better  called  inflammatory cancers.  

            The dramatic response to therapy of childhood cancers and leukemia is ascribed here to the anti-carcinogenic potential of the growing organism.           
 
            Cancer is a metabolic deficiency! (50) This is the modern interpretation of Hippocrates’ 38th aphorism: "It is better not apply any treatment in cases of occult cancer; for if treated,  patients die quickly; but if not treated, they hold out for long time" (51).