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Page 10 of 14 Gottlieb et al. J Cancer Metastasis Treat 2018;4:37 I http://dx.doi.org/10.20517/2394-4722.2018.26
[44]
archies, gene expression stochasticity and protein-protein interactions . However, their roles are not well
defined at present, as in many cases these factors are analyzed as separate events, rather than studying their
[45]
integrated effect on the selection pressures of the complete tissue microenvironment .
One possible hypothesis we have previously proposed is that while intra-tissue genetic heterogeneity may
provide the genetic underpinnings for carcinogenesis. It is tumor microenvironment selection pressure on
preexisting de novo mutations that is the carcinogenic trigger, rather than just the accumulation of de novo
[45]
[46]
mutations . We have further postulated that these mutations occur early in human embryogenesis , as
[47]
has now been suggested in another recent study .
We believe that this hypothesis is supported by the presence of genetic heterogeneity in both cancer and nor-
mal tissues, as well as by the evidence of non-genomic, often environmental factors as risk factors for cancer.
[14]
Indeed, the complexity of post-zygotic variation has only added to the importance of variant selection due
[48]
to environmental factors within tissue microenvironments in determining cancer phenotypes . A detailed
[49]
examination of the arguments favoring a selection-centric paradigm has been given in a recent paper ,
which the identification of AR CSGV in breast tumors has further strengthened.
How the identification of CSGV could affect approaches to cancer treatment
Based on many cases of individual-gene genetic heterogeneity that have recently been identified in normal
as well as cancer tissue, it seems reasonable to believe that CSGV is likely to also occur in normal tissue.
The presence of multiple variants within single genes at low frequencies in normal tissue and cells prior to
tissue becoming cancerous would further strengthen the selection-centric paradigm of carcinogenesis. This
paradigm could also better explain many observations in which, environmental factors that are clearly non-
[50]
mutagenic, i.e., diet, exercise, etc., can somehow direct mutations in specific “driver” genes . Thus, “healthy”
lifestyle factors can result in the selection of environments that are “cancer resistant”, while other environ-
[51]
ments identified as “cancer causing”, that are often man-made, can lead to cancer . CSGV could then sim-
ply explain a “cancer resistant” environment as one that selects for pre-existing wild-type gene variants and
a “cancer causing” environment as one that selects for pre-existing oncogenic gene variants.

Based partially on the principle of parsimony discussed previously, success of species, tissues or cells, has
always been considered to eventually result in a specific species, tissues or cells eliminating the competition.
However, in the case of CSGV this clearly does not seem to be the case, as while gene variants may not be
selected, they are not eliminated entirely either. Thus, in the case of cancer, just destroying the cancer cells
and not changing the conditions that allow for them to be preferentially selected, is possibly going to allow
other cancer cells with different gene variants to eventually be selected, as the environmental conditions that
selected cells with oncogenic properties have not been altered. Our present approach to cancer treatment of
removing cancer cells, does of course not preclude the possibility of cancer recurring. However, the presence
of CSGV would suggest an approach to cancer treatment that in addition to removing the cancer would also
seek to select the normal tissue and cells that are always present within cancer tissues, although normally
only as a very small minority of cells. This new treatment approach would therefore require that cancer tis-
sue microenvironments be returned to conditions that would once again select for normal cells, although
this is clearly not a simple task.

Recently, more attention has started to be given to the carcinogenic role of the tumor microenvironment
[53]
[52]
including in both tumorigenesis and differential tissue responses to therapy . These studies have begun
to analyze and reveal some of the tumor micro-environmental factors that may play a critical role in car-
cinogenesis. Naturally, these data are also likely to help reveal the tissue micro-environmental properties