Abstract
It has been proposed that cell-free nucleic acids in the plasma participate in tumorigenesis and the development of metastases via transfection-like uptake of such nucleic acids by susceptible cells. This putative phenomenon is tentatively referred to as "genometastasis." In the present study, we examined the effects on cultured cells of plasma from healthy individuals and from patients with colon cancer. Cultures of NIH-3T3 cells and human adipose-derived stem cells (hASC) were supplemented with samples of plasma from patients with K-ras-mutated colorectal tumors or from healthy subjects using two different protocols: direct addition of plasma to cultures in standard plates and addition in the absence of contact between plasma and cells, which were separated by a membrane with 0.4-mum pores. In plasma-treated hASCs, no K-ras-mutated sequences were detected by real-time PCR. In contrast, in most cultures of plasma-treated NIH-3T3 cells (murine cells), the transfer of human DNA occurred, as verified by the detection of human K-ras sequences, p53 sequences, and beta-globin-encoding sequences. Moreover, NIH-3T3 cells that had been cultured with plasma from patients with colon cancer were oncogenically transformed, as shown by the development of carcinomas in nonobese diabetic-severe combined immunodeficient mice after the injection of such cells. Microscopic analysis of membranes that had separated plasma from cultured cells confirmed the complete absence of cells in the plasma. We only observed noncell particles, having diameters of <0.4 mum. Our results indicate that plasma from cancer patients is able to transform cultured cells oncogenically, supporting the previously proposed hypothesis of genometastasis.
Highlights
The accepted paradigm of tumor progression, which involves the development of the tumorigenicity and of the invasive capacity of cells at the site of the primary tumor, with subsequent dissemination and metastasis, has been sometimes challenged
NIH3T3 cells that had been cultured with plasma from healthy subjects were positive, in all cases, for human K-ras sequences and negative for mutated K-ras sequences
By real-time PCR, of a point mutation in codon 12 of exon 1 of the human K-ras oncogene (GGT to GAT; Gly to Asp) in cells cultured with human plasma. In this PCR, we examined samples from three plates of NIH-3T3 cells and three plates of human adipose-derived stem cells (hASC) that had been cultured with plasma from patients with colorectal cancer, from three plates of NIH-3T3 cells and three plates of hASCs that had been cultured with plasma from healthy subjects, from a tumor known to have the mutation of interest, and water
Summary
The accepted paradigm of tumor progression, which involves the development of the tumorigenicity and of the invasive capacity of cells at the site of the primary tumor, with subsequent dissemination and metastasis, has been sometimes challenged. 3 decades ago, some authors encouraged to reevaluate the accepted view of the origin and progression of malignant conditions, proposing new exciting theories, such as the horizontal transmission of malignancy [1]. The detection of cell-free nucleic acids in the serum and plasma of cancer patients has aroused considerable interest. Many researchers have tried to determine the clinical value of the detection and quantitation of nucleic acids in the plasma of cancer patients, in particular with respect to the management of such patients, with successful results in some cases [5]. To our knowledge, there are no conclusive data about the role of such nucleic acids in tumor progression
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