Tumor progression to the metastatic state involves structural modifications in DNA markedly different from those associated with primary tumor formation

Polissar

Ostrander

et al. 2000

Structural changes in a 25-base DNA strand, induced by single 8-oxo-guanine or 8-oxo-adenine substitutions, were shown by using Fourier transform-infrared spectroscopy with multivariate statistics. Pronounced differences were demonstrated between the parent and derivatives with respect to base interactions and changes in the phospho-deoxyribose backbone. The greatest degree of change in the backbone likely occurred immediately adjacent to the 8-oxo group, potentially altering the stereochemistry at a distance. The 8-oxo lesions, formed from reactive oxygen species (e.g., hydroxyl radicals), may appreciably alter the conformational properties of strands at the replication fork, thus affecting the selectivity of polymerases, the proofreading capability of repair enzymes, and the fidelity of the transcriptional machinery.Fourier transform-infrared spectroscopy ͉ DNA transcription ͉ DNA replication ͉ DNA repair ͉ DNA polymerases

mentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Single 8-oxo-guanine and 8-oxo-adenine lesions induce marked changes in the backbone structure of a 25-base DNA strand

Polissar

Ostrander

et al. 2000

“…Results and Discussion MCA-Induced DNA Damage Before Tumor Formation. We have demonstrated that the FTIR statistical models of DNA used in this study are capable of identifying a variety of subtle changes in base functional group and backbone structures as well as alterations in conformational properties (20) associated with carcinogenesis (19,21,(23)(24)(25). Specifically, this technology has been used most recently to discriminate between DNA structures of normal prostate tissues, primary tumors, metastasizing primary tumors, and distant metastases of the prostate (18).…”

Section: Methodsmentioning

confidence: 99%

Development of a cancer DNA phenotype prior to tumor formation

Anderson

Gilman

et al. 2004

Using the carcinogen 3-methylcholanthrene (MCA), we demonstrate with Fourier transform-infrared spectroscopy that a cancer DNA phenotype is produced well in advance of palpable tumors. We further demonstrate that the administration of cyclophosphamide markedly inhibits the development of the cancer phenotype and concomitantly delays tumor formation. MCA, injected into the hind legs of mice, produced a variety of significant structural changes in the nucleotide bases and phosphodiester-deoxyribose backbone, as reflected in a substantial (34%) difference between the mean DNA spectra of the control and the MCA-injected mice. Strikingly, 57 days before the mean appearance of tumors, we could not distinguish the DNA structure of the histologically normal tissues of the MCA-injected mice from the DNA structure of the tumor tissues. This finding indicates the early development of a cancer phenotype. Confirmatory evidence was obtained when tissues from a group of mice injected with both MCA and cyclophosphamide did not manifest the cancer phenotype, and their mean DNA structure closely resembled that of the control mice. Accordingly, we propose that the cancer DNA phenotype, as evinced by Fourier transform-infrared spectroscopy, is a promising early indicator of tumor formation, and we postulate that agents capable of inhibiting this phenotype may delay or prevent carcinogenesis.3-methylcholanthrene ͉ antineoplastic agents ͉ cyclophosphamide ͉ cancer inhibition ͉ cancer prediction

“…These structural changes have been found in various stages of primary and metastatic tumor development (10)(11)(12)(13)(14)(15). In a recent study (16), the FTIR technology effectively differentiated between the prostate DNA of histologically normal tissues, nonmetastasizing primary tumors, metastasizing primary tumors, and distant metastases of prostatic carcinomas.…”

mentioning

confidence: 99%

Metastatic cancer DNA phenotype identified in normal tissues surrounding metastasizing prostate carcinomas

Gilman

Green

et al. 2004

Fourier transform-infrared statistical models have the proven ability to identify subtle structural changes in DNA at various stages of tumor development. Using these models, we show evidence for a metastatic cancer DNA phenotype in histologically normal prostate tissues surrounding metastasizing tumors. Strikingly, the DNA base and backbone structures of the metastatic phenotype are indistinguishable from those of the metastasizing prostate tumors but distinctly different from the structure recently reported for the primary cancer DNA phenotype. These findings suggest that the DNA structure linked to the development of metastasis is preordained in progenitor cells relatively early in multistep tumorigenesis. The substantial structural differences found between the primary and metastatic cancer DNA phenotypes suggest that each evolves through a separate pathway. The metastatic phenotype is potentially an early predictor of metastatic disease. Interventions that inhibit its formation would be expected to also inhibit the development of metastatic tumors.metastasis ͉ cancer prediction ͉ cancer intervention ͉ Fourier transforminfrared spectroscopy ͉ DNA structure M etastasis is commonly believed to result from the clonal selection of a few rare cells in a tumor population (1-3). An alternative mechanistic model for metastasis was suggested on the basis of DNA microarray studies implying that the proclivity for metastasis is hardwired in progenitor cells (4-6). One study (4) showed that gene expression profiles in primary breast tumors are strikingly similar to those in distant metastases of the same patients. Another study (7), which used laser capture microdissection in combination with DNA microarrays, found marked similarities at the transcriptional level among the distinct stages of breast tumor progression. Collectively, these studies (4-7) call into question classical theories of metastasis but support the concept that its characteristic features are preordained early in tumorigenesis (8).Statistical models of Fourier transform-infrared (FTIR) spectra of DNA have the unique ability to discriminate between a variety of subtle changes in base functional group and backbone structures as well as in the conformational properties of DNA (9). These structural changes have been found in various stages of primary and metastatic tumor development (10-15). In a recent study (16), the FTIR technology effectively differentiated between the prostate DNA of histologically normal tissues, nonmetastasizing primary tumors, metastasizing primary tumors, and distant metastases of prostatic carcinomas. The first evidence for a primary cancer DNA phenotype in normal tissues was obtained in this study (16). FTIR technology also has been used to distinguish between the DNA of normal granulocytes and granulocytes from patients with myelodysplastic syndrome (17). It was also used recently to identify a primary cancer DNA phenotype in carcinogen-treated mice occurring Ϸ8 weeks before palpable tumors and to show that cyclophosphamide su...