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Yeger et al. J Cancer Metastasis Treat 2020;6:26 I http://dx.doi.org/10.20517/2394-4722.2020.61 Page 9 of 16

chemoprevention has a true functional basis; however, thus far scientists have not been able to propose a
universal working strategy for implementation of cancer chemoprevention.

In addition, the tumor cell (precursor state or subsequently) microenvironment plays a significant role in
how the malignant process evolves and where and how one central player, the cancer associated fibroblasts
[91]
(CAFs), play a major role . Thus in this microenvironment of a developing cancer and thereafter during
tumor progression (with increasing epigenetic aberrations) towards a metastatic phenotype, immune
[92]
surveillance is involved and immune responses are elicited and manipulated . There is a growing
understanding that CAFs play a key role in immunosurveillance in the tumor microenvironment. In
parallel, and even earlier, innate immune responses elicited from the surrounding normal cells would
[93]
cause release of inflammatory mediators necessary for the full- blown immune response . However, in
the resulting complex of immune cells both inhibitors and checkpoints are produced and can suppress
innate immunity. One can therefore surmise that endogenous anti-inflammatory mediators or exogenously
provided as phytochemicals may help modulate the immune response in a positive fashion to thwart
malignant progression and permit rapid return to homeostasis.

In this regard advice has yet to emerge on an appropriate diet that could accurately provide the necessary
dietary phytochemicals that might prove most effective in blocking cancer initiation and progression
and are intrinsically anti-inflammatory [94-97] . Many phytochemicals possess these properties and a routine
intake of the right combinations of phytochemicals that would include the ITCs, well recognized for their
anti-inflammatory activity, might fit the bill. In addition, and for example, as a potential combination
phytochemical, curcumin stands out in this regard . Combinations of phytochemicals, selected
[98]
appropriately, would have a greater inhibitory impact on inflammation, preventively or during progressive
states to limit or inhibit the evolution of a cancer and also thereby the damage to normal tissues [94,99] .
[85]
This has been the working hypothesis favoring the MedDiet. Of concern, as voiced by Tsoupras et al. is
that, if inflammation fails to resolve, due to persistence of a triggering event or unsuccessful block, then
chronic inflammation may exacerbate the damaging outcome. This is where a continuous exposure to
anti-inflammatory phytochemicals could rebalance the inflammatory state. In tumor progression, tumor
cells are able to recruit immune cells to promote tumor progression to a higher state of malignancy and
metastasis . Thus it will be necessary to select phytochemicals, and also other natural compounds,
[13]
that are not only potent anti-inflammatories but also anti-metastatic. In addition, combinations of anti-
inflammatory phytochemicals would likely act additively or synergistically to enhance the positive
outcome. In terms of biomarkers that could identify cancer prevention potential it has been noted that
a pro-coagulative state is related to not only increased risk of cardiovascular diseases but also certain
adult cancers. Grafetstätter et al. [100] assessed lower alcohol and meat consumption population studies that
highlight thrombomodulin and thrombopoietin as two markers that quantitatively associate with chronic
disease development. Thus other biomarkers should be sought that can predict ongoing biological processes
underlying cancer development.

THERAPEUTIC STRATEGY
The cruciferous family of dietary plants provides ITCs, and historically such plants have been used for
medicinals, cooking, and in massage oils from their origins in different members of the cruciferous family.
In addition to these attributes, as an example, benzyl ITC, has shown bacteriostatic, bacteriocidal and
anthelmintic and vermifuge properties at low concentrations. Uppal et al. [101] discuss this but raised the
caveat of poor bioavailability for a number of intrinsic chemical properties . Uppal et al. [101] then showed
[68]
that within a complex of chitosan nanoparticles as carriers there is significantly improved efficacy. In fact,
bio-nanocarriers have proven highly advantageous for efficient delivery of other promising phytochemical
therapeutics such as curcumin [102] . Efforts are being made for improving the bioavailability of ITCs [103] .