Summary and conclusion

In this chapter, a review of general literature, as well as data previously published or unpublished by the author, was presented with the specific aim of fostering an ongoing debate on prostate cancer aetiology. This debate was particularly spurred in the past six years by the controversy arising after isolation of a new retrovirus, highly homologous to endogenous xenotropic and polytropic murine retroviruses, called XMRV [55] [1].

The first part of the chapter has focused on XMRV, its isolation and eventual falsification, also as a "parable" of scientific trajectories and behaviours in science. The most heated episodes are probably missing (but the reader could easily find them in some well-written editorials, for example the one in Science: False Positive, [224]), but the scientific rationale should be easily followed from isolation to falsification. In this first section, I underlined the difference between RNASEL - HPC-1 association and XMRV identification. While the first is rather logically strong and corroborated by several evidence and years of research, the second was essentially based on just one high-throughput technology -kind of shot-in-the-dark- experiment. It is easily biased and prone to artefacts, as it happened in this instance. However, the idea of an infecting agent in PCa is strengthened by several other elements, of which RNASEL involvement is only one (also: IFN, PKR, etc are affected; presence of inflammation, involvement of peripheral prostate, field cancerization effects, etc.).

In the second part, the candidate MFV virus was presented, in view of its affinity with PCa (IFN involvement, RNase-L strong induction, generation of inflammatory mechanisms). For RNase-L, evidence was also coming from CFS studies, again pointing toward similarities between the two conditions (and cancer related fatigue -CRF ? [2] [1]). Furthermore, MFV was isolated from a cancer-cluster (NOT through PCR enrichment) in view of its strong/powerful biological activity. This is exemplified by its very strong apoptogenic mechanisms (entire cultures wiped-out in 36-72 hours) or its capability of inducing strong genetic instability, leading to genomic aberrations, such as MYCN amplification and t(8;14) or t(2;14) [53].

Finally, in the third section, the elements of PCa carcinogenesis, where MFV/MFRVs could show more clearly its effects, were underlined: they included IFN pathways, RNASEL, inflammation and MFV capability of infecting/transforming stem-like cells [53] [55].

What are then the MFV/MFRVs properties which should be emphasized or taken home as messages? Or how we should rationalize them in this ongoing debate on PCa carcinogene-sis ? As mentioned, the RNASEL - HPC-1 paradigm is logically strong and also in CFS numerous evidence point toward infections (micro-epidemics, virus-infection symptoms, IFN pathway etc.) [3] [1].

One essential property of MFV/MFRVs is its biological power, which could lead to strong and persistent infections and long-lasting inflammations in affected hosts. This could easily explain cycles of necrosis/regeneration, which we witness in BPH, PIA, PCa [53] [119].

A second important question -not addressed by this review for limited space- regards the nature of these viruses and whether they have been isolated before. In view of the persis-tent/ long-lasting infections they can initiate, an easy comparison/association is with EBV, which infects H. sapiens in early childhood/youth (depending from geographic areas), then remaining latent, and has been also associated with lymphomagenesis and other human cancers. Indeed, in the hospital-safari's expeditions of Dennis Burkitt, there was a second type and non-Herpes virus (not EBV) constantly isolated [225] [226] [227] [228] [229] [230] [231] [232] (also: Jay Levy/ Thomas Bell, personal communications). All the data available today point toward a virus similar to MFV/MFRVs: in this sense and in view of our MFRVs data, these viruses could be the missing link to malignancy in BL (EBV does not cause malignancy, it just immortalizes lymphoblasts) [53] [233].

A final question, in view of the close relationship of these viruses in terms of persistence in the human population, is what justifies this proximity, which -at least for its "cousin EBV"-resembles parasitism. Several authors and M. Greaves among them, have introduced elements of "Darwinian-medicine" analysis in our interpretation of carcinogenesis [234] [235] [52] [175] [236] [237] [53] [55] [1]. The take-and-give of MFV/MFRVs with H. sapiens infections could certainly be associated to some of their properties. For example, to their strong apop-togenic effects, leading to inflammatory reactions in BPH/PIA/PCa, but also possibly to useful tissue modelling/reshaping in other instances. The described strong relationship of these viruses with stem-like cells further suggests a closer partnership of MFV/MFRVs with H. sapiens in Darwinian-medicine terms. With all possible consequences.

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