Multistep Carcinogenesis: A Chain Reaction of Aneuploidizations

Abstract

Carcinogenesis is a multistep process in which new, parasitic and polymorphic cancer cells evolve from a single, normal diploid cell. This normal cell is converted to a prospective cancer cell, alias "initiated", either by a carcinogen or spontaneously. The initiated cell typically does not have a new distinctive phenotype yet, but evolves spontaneously-over months to decades-to a clinical cancer. The cells of a primary cancer also evolve spontaneously towards more and more malignant phenotypes. The outstanding genotype of initiated and cancer cells is aneuploidy, an abnormal balance of chromosomes, which increases and varies in proportion with malignancy. The driving force of the spontaneous evolution of initiated and cancerous cells to ever more abnormal phenotypes is said to be their "genetic instability". However, since neither the instability of cancer phenotypes nor the characteristically slow kinetics of carcinogenesis are compatible with gene mutation, we propose here that the driving force of carcinogenesis is the inherent instability of aneuploid karyotypes. Aneuploidy renders chromosome structure and segregation errorprone, because it unbalances mitosis proteins and the many teams of enzymes that synthesize and maintain chromosomes. Thus, carcinogenesis is initiated by a random aneuploidy, which is induced either by a carcinogen or spontaneously. The resulting karyotype instability sets off a chain reaction of aneuploidizations, which generate ever more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes. According to this hypothesis the many abnormal phenotypes of cancer are generated by abnormal dosages of thousands of aneuploid, but un-mutated genes. Carcinogenesis is a very rare process in which a normal cell is converted to a cancer cell via multiple "steps" or "stages" of cellular evolution, which correspond to various pre-neoplastic and neoplastic phenotypes and genotypes. 1-4 The clinical and biological phenotypes of the multiple steps of carcinogenesis include hyperplasia, dysplasia, abnormal morphology, anaplasia or dedifferentiation, drug-and multi-drug resistance, immortality, altered histocompatibility including even transplantability to some heterologous species and susceptibility to some heterologous viruses, abnormal metabolism, autonomous growth, invasiveness, and metastasis. 1,5-12 Based on various genetic and cytogenetic markers, including structurally altered or marker chromosomes, most cancers are clonal, i.e., derived from a single cell. 3,13-15 However, a minority is polyclonal. 1,16,17 Despite their clonal origin, "the structure and behavior of tumors are determined by numerous, abnormal characters that, within wide limits, are independently variable, capable of highly varied combinations and assortments and liable to independent progression." 18,19 As a result of this "genetic instability" 3 hardly any two cells from a given cancer are ever the same. 1,20-26,62,137 Indeed, the specific karyotypes and phenotypes of individual cancer cells can v...

Aneuploidy and Cancer: From Correlation to Causation

“…This prediction has been confirmed previously by others [4,10,44,67,70,73,158,[166][167][168] including Boveri, who first demonstrated that X-rays, several chemicals, heat and physical stress generate aneuploidy, but failed to observe cancer in experimental animals [142,143]. However, since these studies did not establish pre-neoplastic aneuploidy as the cause of carcinogenesis [6,7,24,25], we have recently retested the question whether carcinogens cause aneuploidy experimentally, using mutagenic [84] and nonmutagenic carcinogens [169,170], and by reviewing the literature [4,10,25,73,158].…”

“…However, since these studies did not establish pre-neoplastic aneuploidy as the cause of carcinogenesis [6,7,24,25], we have recently retested the question whether carcinogens cause aneuploidy experimentally, using mutagenic [84] and nonmutagenic carcinogens [169,170], and by reviewing the literature [4,10,25,73,158]. These tests have shown that mutagenic carcinogens generate aneuploidy either by breaking and rearranging chromosomal DNA or by chromosome nondysjunction owing to alterations of the spindle apparatus.…”

“…Even immortality is not a selective advantage for carcinogenesis, because many types of human cells can grow over 50 generations according to the Hayflick limit [129], and thus many more generations than are necessary to generate a lethal cancer. Consider that 50 cell generations produce from one single cell a cellular mass equivalent of 10 humans with 10 14 cells each [10]. Nonselective phenotypes, however, are entirely inconsistent with conventional gene mutationselection mechanisms.…”

Detection and Correction of Merotelic Kinetochore Orientation by Aurora B and its Partners

“…2 In addition, aneuploidy is a nearly ubiquitous feature of human cancers 3 and aneuploidy occurring in somatic cells is thought to play a key role in cancer development and/or progression. 4,5 In order to achieve correct chromosome segregation during mitosis, the sister kinetochores, multiprotein complexes that assemble on each chromatid of a replicated chromosome, must interact with microtubules coming from opposite spindle poles, so that the two sister chromatids can be pulled in opposite directions after anaphase onset. Upon nuclear envelope breakdown, dynamically unstable microtubules search the intracellular space until they encounter a kinetochore and capture it.…”

Retinoblastoma epidemiology: Does the evidence matter?

“…55 As more recently reported, 56 cancer appears to begin with epigenetic alterations in stem cells, thus implying that epigenetic (or non mutational) loss of gene expression comes more commonly before any mutations in cancer. 57,58 Also, Duesberg and colleagues [59][60][61][62][63][64][65][66] have heavily argued against the somatic mutation theory by definitely demonstrating that none of the predictions made by that theory is fulfilled by the evidence, 67 thus excluding any possible involvement of somatic mutation, and finally demonstrating and highlighting the fundamental role of aneuploidy in the genesis and progression of cancer. [68][69][70] Aneuploidy is a common feature in the majority of solid human cancers, and several tumour cell lines show chromosome instability (CIN).…”