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CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE |
Chromosomal Instability in Oral Cancer Cells
S.C. Reshmi1 and
S.M. Gollin1,*,2
1 Departments of Human Genetics, University of Pittsburgh Graduate School of Public Health, 130 DeSoto Street, Room A300, and
2 Otolaryngology, and Pathology, the University of Pittsburgh School of Medicine, the Oral Cancer Center at the University of Pittsburgh, and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA;
Correspondence: * corresponding author, sgollin{at}hgen.pitt.edu
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ABSTRACT
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Chromosomal instability is a common feature of human tumors, including oral cancer. Although a tumor karyotype may remain quite stable over time, chromosomal instability can lead to ‘variations on a theme’ of a clonal cell population, often with each cell within a tumor possessing a different karyotype. Thus, chromosomal instability appears to be an important acquired feature of tumor cells, since propagation of such a diverse cell population may facilitate evasion of standard therapies. There are several sources of chromosomal instability, although the primary causes appear to be defects in chromosomal segregation, telomere stability, cell-cycle checkpoint regulation, and the repair of DNA damage. Our understanding of the biological basis of chromosomal instability in cancer cells is increasing rapidly, and we are finding that the seemingly unrelated origins of this phenomenon may actually be related through the complex network of cellular signaling pathways. Here, we review the general causes of chromosomal instability in human tumors. Specifically, we address the state of our knowledge regarding chromosomal instability in oral cancer, and discuss various mechanisms that enhance the ability of cancer cells within a tumor to express heterogeneous karyotypes. In addition, we discuss the clinical relevance of factors associated with chromosomal instability as they relate to tumor prognosis and therapy.
Key Words: cytogenetics • DNA repair • aneuploidy • chromosome segregation • mitotic spindle
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(I) INTRODUCTION
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The field of cancer genetics focuses on processes by which a somatic cell may become transformed through intrinsic DNA alterations, epigenetic changes, structural chromosomal aberrations, and numerical chromosomal changes. Although there is debate regarding how a cell progresses to malignancy, it has been suggested that, aside from normal mutation rates and possible clonal expansion of these mutations, three main sources of error can affect genomic stability in human cancers: nucleotide-excision repair instability (NIN), microsatellite instability (MIN), and chromosomal instability (CIN). Loeb and colleagues refer to these terms collectively as a ‘mutator phenotype’, in which a mutation in any of the genes responsible for maintaining DNA fidelity through replication, repair, chromosome segregation, damage surveillance, or apoptosis may be responsible for human tumor formation and progression (Loeb et al., 2003). While NIN and MIN are primary defects in rare or hereditary cancers containing mutations in DNA mismatch repair genes, CIN occurs in cancers that do not contain nucleotide or microsatellite instability (Lengauer et al., 1998). Recently, Gisselsson reviewed various factors shown to result in, maintain, and enhance CIN (Gisselsson, 2003). Due to the complex nature of CIN, the mechanism(s) by which factors individually and cooperatively promote this phenomenon in cancer are only starting to be elucidated (Fig. ).
Squamous cell carcinoma of the head and neck (SCCHN) and its subset, oral squamous cell carcinoma (OSCC), arise through an accumulation of genetic alterations, including chromosomal alterations, DNA changes (e.g., mutations, amplifications, or deletions), and/or epigenetic alterations, such as changes in methylation that affect genetic regulation. These events are further influenced by exposure to environmental agents, including tobacco smoke, alcoholic beverages, and viruses, such as human papillomavirus (Forastiere et al., 2001; Mork et al., 2001). Previous studies have demonstrated that karyotypes of SCCHN and OSCC consist of near-triploid chromosome numbers and contain various patterns of cytogenetic aberrations, including structural and numerical chromosome abnormalities (Gollin, 2001; Jin et al., 2002). These include, but are not limited to: aneuploidy (gains or losses of whole chromosomes, resulting in a chromosome number altered from that of diploid cells, but which may or may not affect ploidy status [Åkervall et al., 1998]); translocations (balanced or unbalanced re-arrangement of chromosome segments or entire chromosome arms); insertions (breaks either within a chromosome or between two chromosomes, resulting in the direct addition of chromosomal material or, alternatively, the addition of material in the opposite, inverted direction); deletions (loss of small or large DNA segments); and amplifications (multiple additional copies of a specific gene or chromosomal region in the form of extra-chromosomal double minutes [dmin] or intrachromosomal homogeneously staining regions [hsrs]).
Recent investigations have described the presence of mitotic malfunction in tumor cells, including aberrant centrosome numbers, anaphase bridges, multipolar mitotic divisions, and dysfunctional telomeres (Saunders et al., 2000; Gisselsson et al., 2002; Gisselsson, 2003). The following is a review of our current knowledge of factors involved in chromosomal instability, with particular emphasis on oral cancer.
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(II) FACTORS PROMOTING CIN: LOSS OF CELL-CYCLE CONTROL
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(a) Structural Genetic Changes
Alterations in genes governing cell-cycle control provide a green light for continued proliferation of defective cells. Lengauer and colleagues (1998) described four main types of genes which, when altered, promote tumor progression: oncogenes, tumor suppressor genes, DNA repair genes, and those regulating programmed cell death (apoptosis). Tumors displaying complex chromosomal aberrations often contain increased copy numbers of oncogenes known to promote cell differentiation and proliferation, while simultaneously accumulating deletions or loss of genes responsible for detecting DNA damage, halting cell-cycle progression, and/or mediating DNA repair (tumor suppressor genes) in cells prior to replication and/or cell division (Knuutila et al., 1999).
Oncogenes inherently serve to control cellular growth through regulatory pathways. Oncogenes considered to play a role in SCCHN include: growth factor receptors, such as EGFR and ERBB2; intracellular signal transducers, such as RAS family members, RAF1, and STAT3; transcription factors, such as MYC, FOS, JUN, and MYB; cell-cycle regulators such as cyclin D1 (CCND1); and others controlling apoptosis, such as BCL2 and BAX (reviewed in Nagpal and Das, 2003). Alterations in any oncogene through chromosomal translocation, gene amplification, or viral insertion may provide an "on" switch for tumor development and/or progression. Conversely, tumor suppressor genes are negative growth regulators involved in cellular trafficking, regulation of the DNA damage response, and/or apoptosis (Weinberg, 1991). When tumor suppressor gene function or regulation is altered by mutation or hypermethylation (Jain, 2003), the ability to halt the proliferation of damaged cells is lost, allowing unrepaired cells to continue through the cell cycle. Tumor suppressor genes—including FHIT, RB1, TP53, and CDKN2A (p16INK4A)—have been shown to play key roles in HNSCC tumorigenesis (Virgilio et al., 1996; Koontongkaew et al., 2000; Nakahara et al., 2000). Specifically, loss of TP53 function has been shown to correlate with poor response to chemotherapeutic agents such as platinum drugs and fluorouracil, as well as with resistance to radiotherapy (O’Connor et al., 1993; Hamakawa et al., 1998; Temam et al., 2000). In addition, loss of 3p14 and/or 9p21 is considered to be an early event in HNSCC, and, along with TP53 alterations, has been a useful marker for monitoring increased recurrence risk (Brennan et al., 1995; Califano et al., 1996; Gollin, 2001; Rosin et al., 2002).
In the absence of a functional TP53 gene, cells may become aneuploid (Harvey et al., 1993). Studies of colorectal cancer cell lines with MIN have demonstrated that cells with TP53 mutations do not exhibit CIN (Lengauer et al., 1997; Eshleman et al., 1998; Bunz et al., 2002). It is therefore plausible that while defects in cell-cycle checkpoint genes such as TP53 permit cells with CIN to continue through the cell cycle, mutations in genes affecting the mitotic apparatus are more likely to have a direct role in causing the observed CIN in various neoplastic tissues.
(b) Epigenetic Alterations
One of the most common, heritable mechanisms by which gene function can be altered without DNA sequence changes is the process of methylation. The presence of too little or too much methylation may have consequences in tumor cells. For example, undermethylated colorectal tumor cell lines (Lengauer et al., 1997), murine cells lacking DNA methyltransferase (Dnmt1) (Chen et al., 1998; Gaudet et al., 2003) and methylation mutations in immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome (Xu et al., 1999) suggest that methylation defects contribute to genomic instability and CIN. In addition, retroviral integration and subsequent hypomethylation may encourage proto-oncogene activation (Jaenisch et al., 1985). However, while inhibitors of DNA methyltransferase have been shown to be effective in the treatment of some human cancers (Karpf and Jones, 2002), they may actually cause an increased risk of genomic instability in others (Gaudet et al., 2003). Hypermethylation has been shown to affect the fragile histidine triad (FHIT) gene in tumors of the breast and lung by silencing regions that may be important for suppression of tumor growth and proliferation under normal conditions (Zochbauer-Muller et al., 2001; Yang et al., 2002). Recent reports have also demonstrated hypermethylated regions in tumor suppressor genes such as CDKN2B (p15), CDKN2A (p16), and TP53 in oral cancer (Yeh et al., 2003) and hypomethylation of oncogenes in metastatic HNSCC (Smiraglia et al., 2003). Various investigators have suggested that methylation patterns could be useful screening tools for identifying individuals who may be at an increased risk for cancer development (Momparler, 2003; Feinberg and Tycko, 2004).
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(III) FACTORS INDUCING CIN
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(a) Defects in the DNA Damage Response Pathway
Recent studies have revealed that the various cellular pathways appear to be interconnected and/or intertwined. The task of determining which DNA repair genes are involved in tumor progression and CIN remains challenging. Recent examination of faulty double-strand-break (DSB) repair caused by exposure to DNA-damaging agents suggests that neoplasms may arise through factors influencing the ability of a cell to respond to alterations in DNA sequence. Such factors include gene mutation, chromosomal deletions or amplifications, and/or other chromosomal alterations. There are five major DNA repair pathways: homologous recombinational repair (HRR), non-homologous end joining (NHEJ), nucleotide excision repair (NER), base excision repair (BER), and mismatch repair (MMR). Each is comprised of proteins essential for detecting and repairing specific types of DNA damage, but may also promote apoptosis in irreparably damaged cells. A description of these specific repair pathways and pathway components is beyond the scope of this review; however, Bernstein et al.(2002) have published an elegant summary of this topic.
For the purpose of discussing CIN in oral cancer, there are key regulators that sense and respond to DSBs, including the ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins. Both have overlapping as well as unique responses to DNA damage and phosphorylate more than 15 known substrates, including p53, BRCA1, and the CHEK1 and CHEK2 kinases (Shiloh, 2003). Several of these DNA damage response genes—including ATM, TP53, BRCA1, CHEK2, FANC, BLM, and MRE11A—are involved in familial cancer syndromes and may influence CIN (Becker-Catania and Gatti, 2001; Gollin, 2004, 2005). The majority of human tumors carry TP53 mutations or are deficient in proteins that initiate or respond to p53 function (Nigro et al., 1989). The p53 protein plays a major role in directing proteins involved in homologous recombination DSB repair, including LM1, BRCA1, and BRCA2, as well as RAD52, but may also negatively regulate proteins including RAD51 (Buchhop et al., 1997), such that up-regulation of RAD51 in tumors allows for a selective growth advantage for tumor cells in the absence of functional p53 (reviewed in Henning and Stürzbecher, 2003).
Although the relationship between CIN and the DNA damage response is not fully characterized, in light of the findings of Bassing and Celeste and colleagues (Bassing et al., 2003; Celeste et al., 2003), the relationship between haploinsufficiency for critical DNA damage response genes (including ATM, H2AFX, MRE11A, and CHEK1) may be important for tumorigenesis (Gollin, 2004). Since localization of these genes is within the distal region of chromosome 11, which is lost prior to 11q13 gene amplification in almost half of OSCC, haploinsufficiency for these genes may be responsible for some of the observed CIN in oral cancer cells (Gollin and colleagues, unpublished data). Somatic MRE11A mutations in colorectal cancer cell lines suggest a possible causal association between these mutations and CIN, but this remains to be determined (Wang et al., 2004). Interestingly, mice with mutant alleles for MRE11A phenotypically express cell-cycle defects and genomic instability through impaired ATM function, but progress to malignancy only when present on a p53+/– background (Theunissen et al., 2003). Fernandez-Capetillo et al.(2002) demonstrated that, under conditions of increasing DNA damage, H2afx–/– mice with functional Chk2 within the G2-M checkpoint signaling complexes are able to activate DNA repair pathways that do not require H2AX. In addition, the authors showed that H2AX status affects phosphorylation of the DSB signaling protein, Trp5sbp, which has been recognized to affect phosphorylation of Brca1 that is required for both S-phase and G2-M checkpoints following IR-induction (Xu et al., 2002). A more detailed review of the relationship between DNA damage response defects and CIN may be found in Gollin (2004).
(b) Chromosomal Aneuploidy
The term ‘aneuploidy’ refers to an increase or decrease in the number of chromosomes relative to the modal chromosome complement of a particular cell. The presence of chromosomal aneuploidy in both early-stage carcinomas and malignant neoplasms in general suggests its involvement, either directly or indirectly, in tumor progression (Mitelman, 2004). Aneuploidy has been observed in a variety of tumor types, including those of the breast, cervix, esophagus, oral cavity (Gollin, 2001; Jin et al., 2002), prostate, and urothelium (reviewed in Pihan and Doxsey, 1999). Inactivation of several chromosomal segregation-related genes in normal human fibroblasts has been shown to influence early chromosome changes in pre-neoplastic cells. For example, haploinsufficiency for the spindle assembly checkpoint gene, MAD2, results in elevated frequencies of CIN in human cancer cells and murine primary embryonic fibroblasts (Michel et al., 2004). Contrary to other inactivated checkpoint genes, only defects in BUB1 provide cells with the ability to evade apoptosis (Musio et al., 2003). Taken together, these studies suggest that the state of aneuploidy and/or chromosomal instability may be present prior to tumor formation and subsequent proliferation.
Sporadic missegregation, polyploidization, and/or defects in the mitotic apparatus may also promote aneuploidy. Aborted mitosis (restitution) may result in failed formation of the cleavage furrow, leading to numerical doublings of chromosomes and centrosomes, termed ‘tetraploidization’ (Nigg, 2002). This has been observed in a variety of cancers and may give rise to chromosomal aneuploidy through subsequent chromosome loss (Shackney et al., 1995; Galipeau et al., 1996; Southern et al., 1997). Oksala and Therman (1974) described the occurrence of tetraploidization particularly through disrupted cell division. In addition to mitotic arrest, a tetraploid chromosome number may result from failure of mitotic spindle formation (endomitosis), in which cells fall short of undergoing cytokinesis, resulting in a cell containing double the chromosome complement. Tetraploidization may also occur through C-mitosis (spindle arrest in which chromosomes fail to align, resulting in the formation of several micronuclei comprised of the equivalent number of chromosomes in a tetraploid nucleus) or endoreduplication (chromosome replication carried out two times without an interruption by mitosis). Still other cells may undergo amitosis (fusion of two nuclei from different stages of the cell cycle) or tripolar mitoses, the latter of which can result in three daughter cells, two of which may have near-triploid karyotypes and one with a near-diploid karyotype, all exhibiting chromosomal aneuploidy and CIN.
The status of chromosomal ploidy in leukoplakia appears to be an important prognostic marker for oral carcinoma development and progression. Sudbø et al.(2004) carried out a retrospective study designed to assess cancer development in 150 patients with dysplastic oral leukoplakia. Analysis of the data revealed that, of the patients identified with aneuploid epithelial dysplasia, 96% (26/27) developed cancer compared with slightly fewer (80% or 16/20) of those with tetraploid lesions and only 5% (5/103) having diploid lesions. Forty-five of 47 (96%) patients had negative resection margins and post-operative radiotherapy. Of the five patients with a normal diploid chromosomal content, none developed a recurrence following tumor resection. However, more striking were the comparisons between patients with tetraploid lesions and those with aneuploid lesions. The study revealed that 25% (4/16) of patients with tetraploid status developed a recurrence, but survived. This is in sharp contrast to the 26 patients with primary cancers with aneuploidy, of whom 85% (22/26) showed evidence of recurrence and only one survived. Those with lymph node metastasis received one of three chemotherapeutic treatment regimens (methotrexate, docetaxel, or cisplatin). The results suggest that aneuploidy in the target tissue may be a useful predictor of recurrence risk in OSCC, regardless of treatment regimen.
(c) Defects in the Mitotic Apparatus
Karyotypic heterogeneity visualized by interphase cytogenetic analyses suggests that cytoskeletal defects may promote both clonal and non-clonal structural re-arrangements in solid tumors, resulting in daughter cells that do not resemble either each other or their mother cell (reviewed in Pihan and Doxsey, 1999; Reshmi et al., 2004). The mitotic machinery includes microtubules, centrosomes, kinetochores, and molecular motors. Properly choreographed coordination of these structures is essential for accurate chromosome segregation during mitosis. Defective functioning of the mitotic apparatus may permanently influence differences in both chromosome number and structure through subsequent cell divisions.
(1) Microtubules
Microtubules provide ‘tracks’ for chromosome movement, and the microtubule motors carry the chromosome cargo along the tracks (Pihan and Doxsey, 1999). Alterations in microtubules directly resulting in chromosomal aneuploidy have not been demonstrated. However, a study by Lingle et al.(1998) showed that, in breast tumors, increased levels of the centrosomal proteins, centrin and  -tubulin, corresponded with significantly larger-sized centrosomes.
(2) Centrosomes
David Hansemann (1890) was first to report the presence of abnormal mitoses in cancer cells. His findings provided the groundwork for Theodor Boveri’s hypothesis that abnormal centrosome numbers influence chromosome segregation in cancer cells (Boveri, 1914). Subsequent studies have determined that centrosome amplification is indeed an early event in tumor formation (Brinkley, 2001; Lingle et al., 2002) and has been observed in cancers of the brain, bile duct, breast, colon, head and neck, lung, pancreas, and prostate and in human papillomavirus (HPV-16/18) infected cervical cancers (Nigg, 2002). A significant proportion of SCCHN (20–25% of oropharyngeal and 20–50% of tonsillar) are associated with HPV (Gillison et al., 2000; Mork et al., 2001). Furthermore, HPV-positive individuals have a 15-fold increased risk of developing this type of cancer (Mork et al., 2001). However, this has not been proven in other subsets of HNSCC (Gillison et al., 2000). Genetic instability has been shown to occur through expression of the viral oncogenes, E6 and E7 (White et al., 1994). While E6 expression may result in failed cytokinesis, E7 expression may promote uncoupling of the centrosome duplication cycle with the cell division cycle (reviewed in Duensing and Münger, 2001). Despite distinct pathways, both mechanisms may not be mutually exclusive in cancer cells, and may act in combination to drive the CIN phenotype.
Various proteins that associate with centrosomes have been shown to influence centrosome duplication in human cancer. Pericentrin levels were found to be elevated in breast and pancreas tumors (Pihan et al., 1998, 2001; Zhou et al., 1998; Sato et al., 2001; Lingle et al., 2002). CIN has also resulted from alterations of the centrosomal protein, -tubulin, which may be driven by overexpression of DNA polymerase β (Bergoglio et al., 2002).
Overexpression of STK15/BTAK/Aurora -A kinase in human pancreatic cancers (Li et al., 2003) and ovarian cancers (Gritsko et al., 2003) also results in centrosome amplification. Katayama et al.(2004) recently demonstrated a role for aurora A kinase in p53 phosphorylation, subsequently leading to increased Mdm2 binding. Properly functioning Mdm2 targets p53 for ubiquitination and degradation. Thus, the presence of increased levels of aurora A kinase protein, combined with increased Mdm2 expression, results in cells with abnormal centrosomes and aberrant chromosome numbers that continue through the cell cycle by inactivating p53. Of particular interest in this study was the finding that MCF7 breast cancer cells overexpressing aurora A kinase exposed to the DNA-damaging agent, cisplatin, were resistant to apoptosis. Thus, the development of therapeutic agents targeting centrosomal proteins, including aurora A kinase, is warranted.
Other genes that may influence centrosome amplification are key regulators of the DNA damage response pathway and include ATR (Fuchs and Cleveland, 1998), BRCA1 (Schliwa et al., 1999), BRCA2 (Piel et al., 2001), and XRCC2/3 (Griffin et al., 2000). In addition, several genes necessary for protein degradation and mitosis have been shown to contribute to CIN by influencing centrosome numbers (reviewed in Nigg, 2002). Transactivation of TP53, BRCA2, and GADD45 by BRCA1 has been implicated in centrosome amplification (reviewed in Deng, 2002). Conversely, interaction of BRCA1 with RB1 or CDK2 may give rise to cells without centrosome duplication. Although defective genes within the DNA damage response pathway have individually been shown to affect chromosomal instability through improper DNA double-strand-break repair, the exact mechanism by which they act in centrosome amplification remains to be defined (reviewed in Gollin, 2004). However, centrosome amplification has enabled neoplastic progression to be monitored, and has been shown to aid in the prognostic assessment of certain tumor types (Kuo et al., 2000; Pihan et al., 2001), including those of the head and neck (Gustafson et al., 2000; Gisselsson et al., 2002).
(d) Telomere Dysfunction
Telomeres are small repetitive sequences located at the ends of individual chromosomes. Their biological function is to protect chromosome ends from being ‘sticky’ and from shortening at each DNA replication (Blackburn and Challoner, 1984). When telomeres become too short, programmed cell death is initiated through activation of TP53-mediated apoptosis (Chin et al., 1999). In the absence of a functional TP53 checkpoint, tumor cells with shortened telomeres may escape apoptosis. The resulting ‘sticky’, uncapped chromosome ends are then free to associate with each other, causing end-to-end fusions which form dicentric chromosomes. We and others have observed that migration of dicentric chromosomes during cell division may result in anaphase bridges (McClintock, 1938, 1939; Saunders et al., 2000; Gisselsson et al., 2002). The pulling of two active centromeres to opposite poles creates an anaphase bridge, resulting in random, broken chromosome segments within each daughter cell. The free, uncapped ends of these broken chromosomes are then capable of joining with other chromosomes lacking telomeres, giving rise to CIN. If the new chromosome contains two active centromeres, anaphase bridge formation may again occur, promoting breakage-fusion-bridge (BFB) cycles (Chin et al., 1999; Maser and DePinho, 2002). However, some cancer cells may activate the telomere maintenance enzyme, telomerase, which provides a selective growth advantage through telomere stabilization (Meyerson, 1998; Vaziri and Benchimol, 1998). Studies of breast cancer, colorectal cancer, and leukemias have demonstrated that low levels of telomerase are present in pre-neoplastic cells compared with significantly higher levels in advanced-stage tumors (reviewed in Maser and DePinho, 2002). In addition, telomerase status and expression of its subunits, particularly telomerase reverse transcriptase, hTERT, has proved to be a useful prognostic indicator in patients with OSCC (Kannan et al., 1997; Lee et al., 2001). Kannan et al.(1997) observed telomerase activity in normal, hyperplastic, well-differentiated, and moderately or poorly differentiated oral tumors and established a correlation between telomerase activity and OSCC tumor grade. Later, Lee and colleagues demonstrated that 35 of 46 (76%) oral tumors showed hTERT expression and telomerase activity, compared with no activity in the control specimens. Further examination of the relationship between CIN and telomere maintenance is critical to our understanding of the development and propagation of CIN in oral cancer.
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(IV) FACTORS PROPAGATING CIN
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(a) BFB Cycles
One consequence of chromosomal breakage (and or telomere loss) is thought to involve fusion of sister chromatids following replication, giving rise to a dicentric chromosome. At anaphase, the dicentric chromosome may be pulled to opposite poles, resulting in breakage, termed ‘breakage-fusion-bridge’ cycles (McClintock, 1938, 1939). The formation of dicentric chromosomes (Riboni et al., 1997; Artandi et al., 2000; Sawyer et al., 2000) and anaphase bridging (Saunders et al., 2000; Gisselsson et al., 2002) then results in CIN. We and others have shown that BFB cycles may lead to gene amplification (Shuster et al., 2000; Singer et al., 2000), which most likely occurs through sister chromatid fusion (Ma et al., 1993), and to the formation of inverted duplications of the amplified segment. The size of the amplicon is determined by the site(s) of breakage (Toledo et al., 1992; Ciullo et al., 2002). In addition, amplification due to BFB cycles may contain imperfect head-to-head symmetries as well as unequal distances between the amplicon and the telomere in clonal cell populations (Toledo et al., 1992).
(b) Gene Amplification
Gene amplification is a common event in tumors and has been observed both in vivo and in vitro (Stark et al., 1989; Tlsty et al., 1995). Two basic forms of gene amplification have been observed in mammalian cells. Spriggs and colleagues (1962) first described the presence of double minute (dmin) chromosomes in lung tumor cells. Dmin appear as extrachromosomal pairs of chromatin in metaphase cells, and have since been observed in a variety of human malignancies (Schwab, 1999). A second form of gene amplification is present as a uniformly stained and expanded chromosomal band, termed a homogeneously staining region (hsr). Hsrs were first described by Biedler and Spengler (1976) in metaphase cells from antifolate-resistant Chinese hamster lung cells. These hsrs were later shown to correlate with resistance to methotrexate through increased levels of the enzyme, dihydrofolate reductase (Milbrandt et al., 1981). Hsrs are early-replicating (Hamlin and Biedler, 1981; Milbrandt et al., 1981), suggesting that genes residing within the amplified region (amplicon) may have essential roles in regulating cellular functions (Holmquist, 1992). Regardless of the form of amplification, overexpression of genes in dmin or hsrs has been associated with tumor progression (Michalides et al., 1995; Coquelle et al., 1998; Gollin, 2001; Bockmühl et al., 2002). In addition, the presence of gene amplification has proved to be a useful prognostic indicator for overall survival (Field, 1992; Åkervall et al., 1997; Bruckert et al., 2000; Brodeur, 2003) and response to therapy (Pegram et al., 2000).
Amplification of chromosomal band 11q13 in the form of an hsr, and subsequent overexpression of genes therein (Milbrandt et al., 1981; Bartkova et al., 1995), has been observed in approximately 45% of OSCC/SCCHN (Lese et al., 1995; Åkervall et al., 1997; Gollin, 2001; Jin et al., 1998), as well as in carcinomas of the breast, bladder, liver, pancreas, and aerodigestive tract (Schraml et al., 1999). Genes contained in this region include cyclin D1 (CCND1), cortactin (EMS1), fibroblast growth factors 3, 4, and 19 (FGF3 and FGF4, also known as INT2 and HSTF1, FGF19), GARP, and tumor-amplified and overexpressed sequences 1 and 2 (TAOS1 [ORAOV1], TAOS2 [TMEM16A]) (Bekri et al., 1997; Schuuring et al., 1998; Shuster et al., 2000; Huang et al., 2002). The CCND1 gene is an important cell-cycle regulator (Jeannon and Wilson, 1998), and is thought to play a key role in the pathogenesis of OSCC (Michalides et al., 1995; Åkervall et al., 1997) as well as in local recurrence of breast cancer (Champeme et al., 1995). Despite its prevalence, the mechanisms driving gene amplification, which were proposed 20 years ago, are only now becoming clear as a result of our ability to test them using the human genome sequence.
Models for gene amplification propose that initiation of this event may occur through chromosome breakage (Stark, 1993; Coquelle et al., 1997; Pipiras et al., 1998; Ciullo et al., 2002; Tonnies et al., 2003). Other studies have suggested that gene amplification may be the protective response of a cell to treatment with cytotoxic drugs (Stark, 1993; Kuo et al., 1998; Singer et al., 2000; Tonnies et al., 2003) or to oxygen deprivation (Rice et al., 1986; Coquelle et al., 1998). Since both of these factors cause DNA damage resulting in chromosome breakage, the initiating step for gene amplification is proposed to be double-strand breakage. Extra-chromosomal dmin have been shown to re-integrate into the genome at chromosomal fragile sites induced by hypoxia (Coquelle et al., 1998). However, studies have shown that re-integration of dmin chromosomes (Windle et al., 1991) at 11q13 in breast cancers and squamous cell carcinomas is unlikely (Roelofs et al., 1993).
(c) Fragile Sites
Chromosomal fragile sites are sensitive regions of the genome which may form gaps or breaks in metaphase chromosomes when cells are grown under conditions that interfere with DNA replication and/or repair. Common fragile sites occur in all individuals and may be induced in cultured peripheral blood lymphocytes by the inhibition of DNA polymerase- with aphidicolin, followed by ablation of the G2/M checkpoint by the addition of caffeine (Casper et al., 2002). To date, nearly 90 common fragile sites have been identified. Although the current understanding of the structural make-up and function of chromosomal fragile sites remains largely unknown, fragile sites are thought to be the sites of stalled replication forks that result in double-strand breaks (Casper et al., 2002). Thus, a chromosomal re-arrangement at a fragile site may be the result of an attempt to repair a cell exposed to various DNA-damaging agents (Glover, 1998), such as cigarette smoke.
The role of fragile sites in cancer was proposed two decades ago (LeBeau and Rowley, 1984; Yunis and Soreng, 1984). Sutherland et al.(1998) suggested that there may be two roles for fragile sites in cancer. The first may be inactivation of a gene by methylation or deletion at site-specific breaks, in which the critical outcome would be the resulting abnormal gene transcript. Alternatively, fragile sites may result from stalled replication forks or site-specific clastogens, while other drugs may induce random breaks (Coquelle et al., 1997; Casper et al., 2002).
To date, eight common fragile sites have been cloned. These include: FRA3B, FRA6E, FRA6F, FRA7G, FRA7H, FRA9E, FRA16D, and FRAXB (Morelli et al., 2002; Callahan et al., 2003; Denison et al., 2003; Huebner and Croce, 2003). The most widely studied and complex fragile site to date is FRA3B, which contains a gene coding for the fragile histidine triad protein, FHIT. Loss of FHIT has been shown to occur as an early event in small cell lung carcinoma (Whang-Peng et al., 1982), breast cancer (Gatalica et al., 2000), renal cell carcinoma (Velickovic et al., 2001; Sukosd et al., 2003), SCCHN (Virgilio et al., 1996; Gollin, 2001; Jiang et al., 2001; Rosin et al., 2002), and others (Egeli et al., 2000). Recent studies revealed clinical correlations between the FHIT tumor suppressor gene and various cancer types. Although the actual function of FHIT in tumor cells remains unclear, deletions of this locus have been correlated with tumor progression and a poor patient outcome (reviewed in Huebner and Croce, 2003).
Direct evidence has been found to link gene amplification with BFB events involving fragile sites in humans. Ciullo and colleagues (2002) demonstrated that breakage at FRA7I induced amplification of the prolactin-inducible protein (PIP) gene, which is overexpressed in tumors of the prostate and metastatic breast cancer (Autiero et al., 1999; Clark et al., 1999). In addition, Hellman et al.(2002) showed that amplification of the MET oncogene at FRA7G in gastric carcinomas resulted in clustering of recurrent breaks within the FRA7G site, such that amplified segments displayed an inverted repeat pattern, as would be observed as a result of BFB cycles (Shuster et al., 2000; Hellman et al., 2002). Since subsequent breaks are considered to occur randomly as a result of anaphase bridging, BFB cycles may promote heterogeneous amplicon segments (Toledo et al., 1992). Consistent with this are the recent findings of Han et al.(2003), who demonstrated that the tumor suppressor genes, CAV1, CAV2, and TESTIN (TES), contained within the FRA7G site were found to co-amplify and overexpress along with the MET oncogene in a gastric cancer cell line.
Interestingly, four fragile sites have been identified in and around the 11q13 locus: FRA11A at 11q13.3, FRA11B at 11q23.3, FRA11F at 11q14.2, and FRA11H at 11q13 (not mapped to a sub-band). Breakage at FRA11A has been seen to increase in the blood cells of smokers compared with non-smokers (Kao-Shan et al., 1987). The first study to demonstrate an association between a chromosomal fragile site and chromosome breakage in vivo was the characterization of FRA11B, a rare, folate-sensitive fragile site that affects the proto-oncogene, CBL2. This fragile site has been implicated in Jacobsen syndrome through breakage and chromosomal deletion (Jones et al., 1994). Typical features of this disorder include psychomotor delay, trigonocephaly, facial dysmorphism, cardiac defects, and thrombocytopenia, though none appears to occur consistently (Penny et al., 1995). However, genotypic manifestations of most rare fragile sites occur as trinucleotide expansion repeat disorders, rather than loss at a single locus (Jones et al., 2000). Both FRA11H and FRA11F are common fragile sites flanking the region harboring CCND1. Therefore, it is possible that amplification of CCND1 and other genes in band 11q13 may be due to their chromosomal location, surrounded by hotspots for chromosomal breakage. Previous investigations from our laboratory have uncovered proximal and distal breakpoints relative to the commonly amplified 11q13 segment (Huang et al., 2002). Taken together, these findings suggest that two breakage events, perhaps at fragile sites, may occur (1) between the RIN1 and CCND1 genes and (2) distal to the CCND1 gene, resulting in BFB cycles. Studies are under way to confirm the role of 11q13 fragile site breakage in OSCC/SCCHN.
(d) Defective DNA Repair
Chromosomal breakage at or near band 11q13 has been shown to result in loss of the distal segment of chromosome 11 (Jin et al., 1998). Within the chromosomal segment distal to 11q13 are genes required for proper response to DNA damage [see section (IIIa) Defects in the DNA Damage Response Pathway]. These include: MRE11A at 11q21, histone H2AFX at 11q22.3, the ataxia-telangiactasia mutated (ATM) gene at 11q23.2-q23.3, and CHEK1 at 11q24. Although the exact relationship between loss of function of these genes and CIN is currently unclear, the presence of haploinsufficiency for at least one of the DNA damage response genes, H2afx, has been associated with the CIN phenotype in mice (Bassing et al., 2003; Celeste et al., 2003). As discussed earlier, given the observation that 11q13 gene amplification follows loss of distal chromosome 11q (including critical genes involved in the DNA damage response), confirmation of the relationship between haploinsufficiency for distal 11qter and a sluggish DNA damage response may shed light on the biological basis of CIN in OSCC tumor cell progression and metastases.
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(V) SUMMARY
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Chromosomal instability has been shown to play a significant role in the progression of human malignancies. Various factors may induce CIN through DNA double-strand breaks in combination with a defective DNA damage response. In the absence of functioning cellular checkpoints, neoplastic cells with intrinsic chromosomal abnormalities are able to continue through cell division, giving rise to daughter cells that do not resemble either each other or their mother cell. Similarly, extrinsic cytoskeletal aberrations such as multipolar spindles (Saunders et al., 2000), alterations in centrosome number (Gisselsson et al., 2002), or increased expression of centrosomal proteins (Pihan et al., 1998, 2001; Zhou et al., 1998; Sato et al., 2001; Bergoglio et al., 2002; Lingle et al., 2002; Gritsko et al., 2003; Li et al., 2003) may play an important role in CIN. Regardless of how the observed mutator phenotype originates, propagation of these chromosomal defects is maintained through BFB cycles, which may in turn promote further CIN through gene amplification (Coquelle et al., 1997, 1998; Shuster et al., 2000; Ciullo et al., 2002; Hellman et al., 2002).
Despite ongoing clinical trials in gene therapy, immunotherapy, and molecular-based agents for the effective treatment of SCCHN, the heterogeneous nature of the cell populations within these tumors challenges the success of therapies targeted at specific genes. However, some progress has been made. Due to the recently identified connection between the cell-cycle checkpoints and the DNA damage response pathway, additional therapies targeting checkpoint kinases such as CHEK1 and CHEK2 may chemosensitize cancer cells defective in the G2/M checkpoint and improve the overall prognosis for oral cancer patients (Zhou and Sausville, 2003). Other cancer therapies focusing on the mitotic apparatus have proved to be effective for some cancers (Eckhardt, 2002; Walczak and Carducci, 2002). For example, microtubule inhibitors, such as taxanes (Paclitaxel, Docetaxel) and Vinca alkaloids (Vindesine, Vinorelbine), promote mitotic arrest and induce apoptosis and are used to treat solid tumors of the breast, esophagus, prostate, and lung (Walczak and Carducci, 2002). Moreover, drugs such as VX-680 that inhibit Aurora kinases and subsequently suppress tumor growth in vivo are on the horizon (Harrington et al., 2004). Thus, further insight into the mechanisms driving CIN may undoubtedly provide opportunities for investigators to identify new biomarkers to aid in diagnosis and prognosis, and achieve the ultimate goal of developing novel therapeutic strategies for patients with SCCHN.
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ACKNOWLEDGMENTS
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The authors are grateful to their enthusiastic colleagues, collaborators, and trainees—Drs. William Saunders, Xin Huang, Tony Godfrey, Baskaran Rajasekaran, Michele Shuster, Christa Lese-Martin, and Rahul Atul Parikh—in investigating the biologic basis of chromosomal instability in oral cancer cells. We thank Mr. David W. Schoppy for assistance with manuscript preparation. The authors are supported in part by NIH Grants R01DE14729 to S.M.G., P30CA47904 to R.B. Herberman, and P60DE13059 to E.N. Myers. Funding from the National Institute of Dental and Craniofacial Research (NIDCR) has been instrumental in our understanding of chromosomal instability in oral cancer cells and continues to support ongoing investigations in this important topic. Special gratitude is due to Drs. Ann Sandberg and Yasaman Shirazi of the NIDCR. The authors are also grateful to the Stout Family Fund for Head and Neck Cancer Research at the Eye and Ear Foundation of Pittsburgh.
Received for publication January 5, 2004.
Accepted for publication March 22, 2004.
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Journal of Dental Research, Vol. 84, No. 2,
107-117 (2005)
DOI: 10.1177/154405910508400203
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ABSTRACT
(I) INTRODUCTION