Cancer Progression Mediated by Horizontal Gene Transfer in an In Vivo Model

Abstract

It is known that cancer progresses by vertical gene transfer, but this paradigm ignores that DNA circulates in higher organisms and that it is biologically active upon its uptake by recipient cells. Here we confirm previous observations on the ability of cell-free DNA to induce in vitro cell transformation and tumorigenesis by treating NIH3T3 recipient murine cells with serum of colon cancer patients and supernatant of SW480 human cancer cells. Cell transformation and tumorigenesis of recipient cells did not occur if serum and supernatants were depleted of DNA. It is also demonstrated that horizontal cancer progression mediated by circulating DNA occurs via its uptake by recipient cells in an in vivo model where immunocompetent rats subjected to colon carcinogenesis with 1,2-dimethylhydrazine had increased rate of colonic tumors when injected in the dorsum with human SW480 colon carcinoma cells as a source of circulating oncogenic DNA, which could be offset by treating these animals with DNAse I and proteases. Though the contribution of biologically active molecules other than DNA for this phenomenon to occur cannot be ruled out, our results support the fact that cancer cells emit into the circulation biologically active DNA to foster tumor progression. Further exploration of the horizontal tumor progression phenomenon mediated by circulating DNA is clearly needed to determine whether its manipulation could have a role in cancer therapy.

Circulating tumour DNA: a minimally invasive biomarker for tumour detection and stratification

“…A study by Garcia-Olmo et al (2010) have demonstrated the potential of plasma DNA to transfect and oncogenically transform susceptible cells, and showed that plasma of colon cancer patient selectively transforms NIH/3T3 mouse cells while having no effect on human adipose-derived stem cells. Similar findings were also reported by Trejo-Becerril et al (2012) in an in vivo immunocompetent coloncarcinogenesis rat model. However, a number of observations have limited the validity of this hypothesis.…”

Cell-free DNA (cfDNA): Clinical Significance and Utility in Cancer Shaped By Emerging Technologies

“…It has also been suggested, that another important function of the DNaseI-based mechanism of clearing cfDNA from human blood is the prevention of autoimmunity against DNA (47). Involvement of cfDNA was suggested for other biological processes as well, ranging from tumor dissemination (2,(48)(49)(50) to aging (51), but experimental evidence supporting such hypotheses remains tenuous, and considerable additional research is needed to clarify the involvement of cfDNA in processes other than immunologic response.…”

A historical and evolutionary perspective on the biological significance of circulating DNA and extracellular vesicles

“…To date, there is no direct evidence that mutated cirDNA can initiate metastases. However, studies later confirmed that cirDNA (k-ras codon 12 mutated DNA) can promote tumor progression via lateral gene transfer (LGT) in rats that already have developed tumors, but does not itself initiate tumor formation in the host animal [117]. This concept of tumorigenic DNA being involved in cancer metastasis correlates so effectively with Darwin's gemmules that one cannot help but agree with Liu [118] that gemmules are analogues to cirNAs.…”