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

Abstract

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...

A cancer DNA phenotype in healthy prostates, conserved in tumors and adjacent normal cells, implies a relationship to carcinogenesis

“…However, we have reported previously (2,5,24) the ability to differentiate the DNA of prostate tumors with evidence of metastasis from those without such evidence. In this regard, a metastatic cancer DNA phenotype (structurally indistinguishable from the tumor DNA) was identified in histologically normal tissues surrounding prostate tumors having confirmed distant metastases (5).…”

“…tical models (1)(2)(3)(4)(5), we have demonstrated previously a cancer DNA phenotype in the limbs of mice 10 weeks after injecting the carcinogen 3-methylcholanthrene (4). This phenotype was identified in normal tissues 8 weeks before tumor formation.…”

Oxidative Changes in the DNA of Stroma and Epithelium from the Female Breast: Potential Implications for Breast Cancer

“…23 Spectral analysis was performed using an FT-IR microscope spectrometer (System 2000, PerkinElmer). 24 Spectral measurements were converted (Fourier-transformed) into absorbance. Each spectrum was then baselined and normalized between 1750 and 760 cm -1 .…”

Nitric oxide and metastatic cell behaviour

“…Metastatic potential may arise as a result of multiple mutations accumulated during proliferative activity of a tumour cell population (5) and/or, according to more recent hypotheses, in fact, may be pre-determined in the primary tumour. (6) Epigenetic changes (i.e. changes in levels of gene expression that occur without any alteration of DNA sequence) are also responsible for malignancy and cancer progression.…”