Specific aneusomies in Chinese hamster cells at different stages of neoplastic transformation, initiated by nitrosomethylurea

Abstract

Aneuploidy is ubiquitous in cancer, and its phenotypes are inevitably dominant and abnormal. In view of these facts we recently proposed that aneuploidy is sufficient for carcinogenesis generating cancerspecific aneusomies via a chain reaction of autocatalytic aneuploidizations. According to this hypothesis a carcinogen initiates carcinogenesis via a random aneuploidy. Aneuploidy then generates transformation stage-specific aneusomies and further random aneusomies autocatalytically, because it renders chromosome segregation and repair mechanisms error-prone. The hypothesis predicts that several specific aneusomies can cause the same cancers, because several chromosomes also cooperate in normal differentiation. Here we describe experiments on the Chinese hamster (CH) that confirm this hypothesis. (i) Random aneuploidy was detected before transformation in up to 90% of CH embryo cells treated with the carcinogen nitrosomethylurea (NMU). (ii) Several specific aneusomies were found in 70 -100% of the aneuploid cells from colonies transformed with NMU in vitro and from tumors generated by NMUtransformed cells in syngeneic animals. Among the aneuploid in vitro transformed cells, 79% were trisomic for chromosome 3, and 59% were monosomic for chromosome 10, compared with 8% expected for random distribution of any aneusomy among the 12 CH chromosomes. Moreover, 52% shared both trisomy 3 and monosomy 10 compared with 0.6% expected for random distribution of any two aneusomies. Among the tumor cells, 65% were trisomic for chromosome 3, 51% were trisomic for chromosome 5, and 30% shared both trisomies. Aneuploid cells without these specific aneusomies may contain minor transformation-specific aneusomies or may be untransformed. (iii) Random aneusomies and structurally altered chromosomes increased with the generations of transformed cells to the point where their origins became unidentifiable in tumors. We conclude that specific aneusomies are necessary for carcinogenesis.

Aneuploidy and Cancer: From Correlation to Causation

“…Despite the karyotypic instability and heterogeneity of cancer cells partially specific or nonrandom aneuploidies have been found in cancers since in the late 1960s [61,62,[76][77][78][79][80][81][82][83][84][85][86][87]. Since the 1990s, many more nonrandom aneuploidies have been detected in cancers by the use of comparative genomic hybridization, rather than by identifying specific aneusomies cytogenetically [61,[88][89][90][91][92][93][94][95][96].…”

“…The term aneusomy is used for a specific, aneuploid chromosome. Specific aneuploidies have even been linked with specific stages of carcinogenesis and with specific phenotypes of cancers such as: (1) Distinct stages of neoplastic transformation in human [62,89,[95][96][97][98][99] and in animal carcinogenesis [84]; (2) invasiveness [97,98,100]; (3) metastasis [101][102][103][104][105][106]; (4) drug-resistance [53,69,107]; (5) transplantability to foreign hosts [108]; (6) distinct cellular morphologies [109]; (7) abnormal metabolism [62,110], and (8) cancer-specific receptors for viruses [62,109].…”

“…This theory, however, was abandoned in the 1950s and 1960s in favor of mutation, because instead of the expected cancer-specific aneuploidy, karyotypic heterogeneity was found in most cancers by the methods developed at that time [62,144,145]. Ever since, 'aneuploidy and other forms of chromosomal abnormality' of cancer cells [56] are generally interpreted as 'secondary' events [24,56,61,62,146] -secondary to presumably primary gene mutations [15,32,64,75,[147][148][149][150][151][152][153]; (4) cancer-specific aneuploidies discovered since the late 1960s by many laboratories including ours, particularly by comparative genomic hybridizations [84]. These discoveries, however, are not appreciated as chromosomal causes of cancer because of the prevailing genetic theories.…”

“…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.…”

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).…”