The mutator phenotype theory can explain the complex morphology and behaviour of cancers

Almost all solid malignancies exhibit complex cytological and architectural abnormalities, which vary from cell to cell and area to area within the same tumour, and between tumours of the same type. The degrees of these abnormalities do not correlate perfectly with the biological behaviour (especially growth rate and metastatic potential) among the various tumour types. These features of tumours have long been considered to invalidate simple mutational or 'abnormal gene expression' (epigenetic) theories of carcinogenesis. The 'mutator phenotype/clonal selection' hypothesis is based on the now well-established phenomenon of genetic instability of cancer cells, and proposes that this instability is an essential requirement for the development of tumours, and not an irrelevant side-effect of some other process. This paper argues that this hypothesis can provide a satisfactory explanation for the diverse histological and biological features of solid malignancies. Further, because virtually all solid tumours are histologically abnormal, genetic instability is likely to be essential for the malignant process. The concepts of mutator phenotype and clonal selection are therefore supported. Received 8 April 2002; accepted 25 April 2002     

The FHIT gene product: tumor suppressor and genome “caretaker”

The FHIT gene at FRA3B is one of the earliest and most frequently altered genes in the majority of human cancers. It was recently discovered that the FHIT gene is not the most fragile locus in epithelial cells, the cell of origin for most Fhit-negative cancers, eroding support for past claims that deletions at this locus are simply passenger events that are carried along in expanding cancer clones, due to extreme vulnerability to DNA damage rather than to loss of FHIT function. Indeed, recent reports have reconfirmed FHIT as a tumor suppressor gene with roles in apoptosis and prevention of the epithelial–mesenchymal transition. Other recent works have identified a novel role for the FHIT gene product, Fhit, as a genome “caretaker.” Loss of this caretaker function leads to nucleotide imbalance, spontaneous replication stress, and DNA breaks. Because Fhit loss-induced DNA damage is “checkpoint blind,” cells accumulate further DNA damage during subsequent cell cycles, accruing global genome instability that could facilitate oncogenic mutation acquisition and expedite clonal expansion. Loss of Fhit activity therefore induces a mutator phenotype. Evidence for FHIT as a mutator gene is discussed in light of these recent investigations of Fhit loss and subsequent genome instability.     

Initiation of genetic instability and tumour formation: a review and hypothesis of a nongenotoxic mechanism

Genetic instability in tumours results in cell-to-cell variability of genome which parallels the cell-to-cell variability of microscopic morphology and of behaviour (tumour cell heterogeneity) of these lesions. Genetic instability is therefore strongly supported as the fundamental process by which normal tissue cells become neoplastic. The commonest current suggestion for the mechanism of initiation of carcinogenesis is a 'direct hit' mutation of a 'cancer critical' gene in a somatic cell by carcinogenic agents. However, this mechanism does not account for the activity of carcinogens which are not mutagens, and does not explain why many mutagens are not carcinogens. This paper proposes a nonmutational (nongenotoxic) mechanism of initiation of genetic instability in previously normal cells as follows: 1) During S phase of local tissue stem cells, carcinogen binds to and disables the proofreading enzyme for a new DNA strand. 2) While it is disabled, the proofreading enzyme fails to correct illicit changes in the nucleotide sequence(s) for one or more genes for proofreading fidelity or repair of DNA in the new strand of DNA, which passes to one daughter cell. 3) When this daughter cell is a continuing stem cell, the resulting cell line remains immortal, and retains its prior differentiation commitment to produce daughter cells of a particular type. However, the acquired genetic instability in this cell line causes secondary mutations which lead to uncontrolled growth, and the heterogeneous morphologic and behavioural features of a tumour resembling the parent cell type.     

Welcome the Family of FANCJ-like Helicases to the Block of Genome Stability Maintenance Proteins

The FANCJ family of DNA helicases is emerging as an important group of proteins for the prevention of human disease, cancer, and chromosomal instability. FANCJ was identified by its association with breast cancer, and is implicated in Fanconi Anemia. Proteins with sequence similarity to FANCJ are important for maintenance of genomic stability. Mutations in genes encoding proteins related to FANCJ, designated ChlR1 in human and Chl1p in yeast, result in sister chromatid cohesion defects. Nematodes mutated in dog-1 show germline as well as somatic deletions in genes containing guanine-rich DNA. Rtel knockout mice are embryonic lethal, and embryonic stem cells show telomere loss and chromosomal instability. FANCJ also shares sequence similarity with human XPD and yeast RAD3 helicases required for nucleotide excision repair. The recently solved structure of XPD has provided new insight to the helicase core and accessory domains of sequence related Superfamily 2 helicases. The functions and roles of members of the FANCJ-like helicase family will be discussed. Received 17 September 2008; received after revision 24 October 2008; accepted 28 October 2008     

Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers

Breast and ovarian cancer are among the most common malignancies diagnosed in women worldwide. Together, they account for the majority of cancer-related deaths in women. These cancer types share a number of features, including their association with hereditary cancer syndromes caused by heterozygous germline mutations in BRCA1 or BRCA2. BRCA-associated breast and ovarian cancers are hallmarked by genomic instability and high sensitivity to DNA double-strand break (DSB) inducing agents due to loss of error-free DSB repair via homologous recombination (HR). Recently, poly(ADP-ribose) polymerase inhibitors, a new class of drugs that selectively target HR-deficient tumor cells, have been shown to be highly active in BRCA-associated breast and ovarian cancers. This finding has renewed interest in hallmarks of HR deficiency and the use of other DSB-inducing agents, such as platinum salts or bifunctional alkylators, in breast and ovarian cancer patients. In this review we discuss the similarities between breast and ovarian cancer, the hallmarks of genomic instability in BRCA-mutated and BRCA-like breast and ovarian cancers, and the efforts to search for predictive markers of HR deficiency in order to individualize therapy in breast and ovarian cancer.     

Microsatellite instability in gastric cancer: molecular bases,clinical perspectives,and new treatment approaches

Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.     

Tumor microenvironment: becoming sick of Myc

Several years ago, we described Myc as “the oncogene from hell”, since evidence had just emerged that Myc, aside from being responsible for cell-cycle progression and tumor expansion, was also able to induce genomic instability in culture, wreaking havoc in tumor cells and accelerating tumor progression (Soucek and Evan, Cancer Cell 1:406–408, 2002; Vafa et al., Mol Cell 9:1031–1044, 2002). In this review, we discuss recent publications that expand Myc’s evil armory to include coordination of the crosstalk between tumor and microenvironment. Indeed, endogenous Myc, acting as a client for upstream oncogenic lesions, instructs the tumor stroma, engages a complex inflammatory response and induces angiogenesis, thus allowing the tumor to thrive. This is highly topical in light of the fact that Hanahan and Weinberg have recently redefined the hallmarks of cancer and pointed out that genomic instability and inflammation are essential for both their acquisition and development (Hanahan and Weinberg, Cell 144:646–674, 2011). Myc, it seems, is behind it all.     

Modifiers of radiosensitivity

Conclusion Many different methods exist by which the radiosensitivity of cells, and hence of normal tissues and tumours, can be manipulated. Several of these can be traced to a common redox pathway involving competition between oxidising and reducing species. Others involve the biochemical enzyme systems required for removal of DNA lesions. At the present time most of these approaches are still actively undergoing basic research studies and have not found full application in cancer clinics. For any such approach to be of therapeutic use there must be a rationale for a differential effectiveness in tumours and normal tissues.     

Cyclosporine resistant effector cells in rabbit skin allografts

Histoincompatible skin grafts in rabbits treated with cyclosporine can permanently engraft but show a transient mononuclear cellular infiltrate. This transient cyclosporine-resistant infiltrate consists of cells which are sensitive to steroids, radiation and cryopreservation. They have the same ACM-1 phenotype and the same characteristics as cyclosporine-sensitive cells.     

Platelets as crucial partners for tumor metastasis: from mechanistic aspects to pharmacological targeting

Platelets are anucleated cells that circulate in the blood as sentinels of tissue integrity. In fact, they are rich in a plethora of proteins and other factors stored in different granules which they selectively release upon stimulation. Moreover, platelets synthesize a vast number of lipids and release various types of vesicles, including exosomes which are rich in genetic material. Platelets possess a central function to interact with other cell types, including inflammatory cells and cancer cells. Recent findings have enlightened the capacity of platelets to induce changes in the phenotype of cancer cells which acquire invasiveness thus enhancing their metastatic potential. Thus, it has been hypothesized that targeting the platelet may represent a novel strategy to prevent the development and progression of cancer. This is supported by the efficacy of the antiplatelet agent low-dose aspirin. Studies are ongoing to verify whether other antiplatelet agents share the anticancer effectiveness of aspirin.     

Molecular and Cellular Basis of Regeneration and Tissue Repair

The ability to produce differentiated cell types at will offers one approach to cell therapy and therefore the treatment and cure of degenerative diseases such as diabetes and liver failure. Until recently it was thought that differentiated cells could only be produced from embryonic or adult stem cells. However, we now know that this is not the case, and there is a growing body of evidence to show that one differentiated cell type can convert into a completely different phenotype (transdifferentiation). Understanding the cellular and molecular basis of transdifferentiation will allow us to reprogram cells for transplantation. This approach will complement the use of embryonic and adult stem cells in the treatment of degenerative disorders. In this review, we will focus on some well-documented examples of transdifferentiation.     

What mechanisms/processes underlie radiation-induced genomic instability?

Radiation-induced genomic instability is a modification of the cell genome found in the progeny of irradiated somatic and germ cells but that is not confined on the initial radiation-induced damage and may occur de novo many generations after irradiation. Genomic instability in the germ line does not follow Mendelian segregation and may have unpredictable outcomes in every succeeding generation. This phenomenon, for which there is extensive experimental data and some evidence in human populations exposed to ionising radiation, is not taken into account in health risk assessments. It poses an unknown morbidity/mortality burden. Based on experimental data derived over the last 20?years (up to January 2012) six mechanistic explanations for the phenomenon have been proposed in the peer-reviewed literature. This article compares these hypotheses with the empirical data to test their fitness to explain the phenomenon. As a conclusion, the most convincing explanation of radiation-induced genomic instability attributes it to an irreversible regulatory change in the dynamic interaction network of the cellular gene products, as a response to non-specific molecular damage, thus entailing the rejection of the machine metaphor for the cell in favour of one appropriate to a complex dissipative dynamic system, such as a whirlpool. It is concluded that in order to evaluate the likely morbidity/mortality associated with radiation-induced genomic instability, it will be necessary to study the damage to processes by radiation rather than damage to molecules.     

The origin of experimental brain tumours: A sequential study

A sequential study of rat brains treated transplacentally with the neurotropic carcinogen ethylnitrosourea reveals small foci of cell proliferations from the age of 8 weeks. These lesions consist mainly of undifferentiated cells of the subependymal plate type. They occur in those areas in which gliomas develop and represent the earliest, histologically detectable, changes in the development of brain tumours.     

Activation of the human FP prostanoid receptor disrupts mitosis progression and generates aneuploidy and polyploidy

Studies have shown prostaglandin F_2α to be an endogenous tumor promoter in mouse models of skin carcinogenesis; however, the mechanisms by which PGF_2α affects cell cycle events remain unknown. Here we performed cell cycle analyses on HEK cells stably expressing the human FP receptor and found that treatment with PGF_2α delays mitosis and is associated with an increased expression of cyclin B1 and Cdc2 kinase activity. In addition, multipolar spindles and misaligned chromosomes were observed in a significant proportion of cells treated with PGF_2α. Defective cytokinesis was also observed which resulted in gross aneuploidy and polyploidy. Expression of dominant negative Rho attenuated the cell cycle delay and prevented the generation of micronuclei following treatment with PGF_2α. This suggests that FP receptor activation of Rho signaling by PGF_2α can interfere with nuclear division. Aneuploidy is associated with genomic instability and may underlie the tumor-promoting properties of PGF_2α. Received 7 July 2005; received after revision 22 October 2005; accepted 11 November 2005     

Cyclosporine resistant effector cells in rabbit skin allografts

Summary Histoincompatible skin grafts in rabbits treated with cyclosporine can permanently engraft but show a transient mononuclear cellular infiltrate. This transient cyclosporine-resistant infiltrate consists of cells which are sensitive to steroids, radiation and cryopreservation. They have the same ACM-1 phenotype and the same characteristics as cyclosporine-sensitive cells.9 January 1987Supported by the Swiss National Research Foundation, Grant No. 3.908-0.83.     

RecQ helicases and topoisomerases: components of a conserved complex for the regulation of genetic recombination

Maintenance of genomic stability relies on the efficient and accurate execution of DNA repair pathways, and is essential for cell viability and the prevention of cancer. Mutation of genes encoding RecQ helicases or topoisomerases gives rise to genomic instability through excessive recombination. Here, we review the recent biochemical and genetic evidence to indicate that these two classes of protein act in concert in a conserved pathway to maintain genomic stability by preventing inappropriate recombination.     

Updating the mechanisms of common fragile site instability: how to reconcile the different views?

Common fragile sites (CFSs) are large chromosomal regions long identified by conventional cytogenetics as sequences prone to breakage in cells subjected to replication stress. The interest in CFSs came from their key role in the formation of DNA damage, resulting in chromosomal rearrangements. The instability of CFSs was notably correlated with the appearance of genome instability in precancerous lesions and during tumor progression. Identification of the molecular mechanisms responsible for their instability therefore represents a major challenge. A number of data show that breaks result from mitotic entry before replication completion but the mechanisms responsible for such delayed replication of CFSs and relaxed checkpoint surveillance are still debated. In addition, clues to the molecular events leading to breakage just start to emerge. We present here the results of recent reports addressing these questions.