Abstract

Introduction

Cancer is a disease involving multiple time- and space-dependent changes in the health status of cells and tissues that ultimately lead to malignant tumors. Neoplasia (abnormal cell growth) is the biological endpoint of the disease. Tumor cell invasion into surrounding tissues and their spread (metastasis) to distant organs is the primary cause of morbidity and mortality of most cancer patients ( 1-5 ). A major impediment in the effort to control cancer has been due in large part to the confusion surrounding the origin of the disease. Contradictions and paradoxes continue to plague the field ( 6-10 ). Much of the confusion surrounding cancer origin arises from the absence of a unifying theory that can integrate the many diverse observations on the nature of the disease. Without a clear understanding of how cancer arises, it becomes difficult to formulate a successful strategy for effective long-term management and prevention. The failure to clearly define the origin of cancer is responsible in large part for the failure to significantly reduce the death rate from the disease ( 2 ). Although cancer metabolism is receiving increased attention, cancer is generally considered a genetic disease ( 10 , 11 ). This general view is now under serious reevaluation ( 2 , 12 ). The information in this review comes in part from our previous articles and treatise on the subject ( 2 , 13-17 ).

Provocative question: does cancer arise from somatic mutations?

Most of those who conduct academic research on cancer would consider it a type of somatic genetic disease where damage to a cell’s nuclear DNA underlies the transformation of a normal cell into a potentially lethal cancer cell ( 7 , 10 , 11 , 18 ). Abnormalities in dominantly expressed oncogenes and in recessively expressed tumor suppressor genes have been the dogma driving the field for several decades ( 7 , 10 ). The discovery of millions of gene changes in different cancers has led to the perception that cancer is not a single disease, but is a collection of many different diseases ( 6 , 11 , 19 , 20 ). Consideration of cancer as a ”˜disease complex’ rather than as a single disease has contributed to the notion that management of the various forms of the disease will require individual or ”˜personalized’ drug therapies ( 2 , 21-23 ). Tailored therapies, unique to the genomic defects within individual tumors, are viewed as the future of cancer therapeutics ( 2 , 24 ). This therapeutic strategy would certainly be logical if the nuclear somatic mutations detected in tumors were the drivers of the disease. How certain are we that tumors arise from somatic mutations and that some of these mutations drive the disease? It would therefore be important to revisit the origin of the gene theory of cancer.

The gene theory of cancer originated with Theodor Boveri’s suggestion in 1914 that cancer could arise from defects in the segregation of chromosomes during cell division ( 18 , 25-29 ). As chromosomal instability in the form of aneuploidy (extra chromosomes, missing chromosomes or broken chromosomes) is present in many tumor tissues ( 21 , 30-32 ), it was logical to extend these observations to somatic mutations within individual genes including oncogenes and tumor suppressor genes ( 18 , 33-36 ). Boveri’s hypothesis on the role of chromosomes in the origin of malignancy was based primarily on his observations of chromosome behavior in nematodes ( Ascaris ) and sea urchins ( Paracentrotus ) and from his consideration of von Hansemann’s earlier observations of abnormal chromosome behavior in tumors ( 18 , 25 , 29 ). In contrast to Boveri’s view of aneuploidy as the origin of cancer, von Hansemann considered the abnormal chromosome behavior in tumors as an effect rather than as a cause of the disease ( 25 ). Although Boveri’s hypothesis emerged as the foundation for the somatic mutation theory of cancer, it appears that he never directly experimented on the disease ( 18 , 25 , 29 ). The reason for the near universal acceptance of Boveri’s hypothesis for the origin of cancer is not clear but might have been linked to his monumental achievement in showing that Gregor Mendel’s abstract heredity factors resided on chromosomes ( 29 ). Boveri’s cancer theory was also consistent with the gradual accumulation of evidence showing that DNA abnormalities are abundant in cancer cells.

In his 2002 review, Knudson stated that, ”˜considerable evidence has been amassed in support of Boveri’s early hypothesis that cancer is a somatic genetic disease’ ( 37 ). The seeds of the somatic mutation theory of cancer might have been sowed even before the work of von Hansemann and Boveri. Virchow considered that cancer cells arose from other cancer cells ( 38 ). Robert Wagner provided a good overview of those early studies leading to the idea that somatic mutations give rise to cancer ( 38 ). It gradually became clear that almost every kind of genomic defect could be found in tumor cells whether or not the mutations were connected to carcinogenesis ( 10 , 11 , 18 , 26 , 31 ). The current somatic mutation theory involves a genomic landscape of incomprehensible complexity that also includes mysterious genomic ”˜Dark Matter’ ( 2 , 10 , 11 , 19 ). Although massive evidence exists showing that genomic instability is present to some degree in all tumor cells, it is unclear how this phenotype relates to the origin of the disease. It appears that almost every neoplastic cell within a naturally arising human tumor is heterogeneous in containing a unique genetic architecture ( 31).