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Page 8 of 16 Yeger et al. J Cancer Metastasis Treat 2020;6:26 I http://dx.doi.org/10.20517/2394-4722.2020.61
[82]
mitohormesis such as FGF21 and GDF15 have been described vis-à-vis increased lifespan . It is also
proposed that altered mitohormesis primes a subpopulation of cancer cells to upregulate mitochondrial
[83]
stress response leading to an adaptive metastatic phenotype . Therefore, theoretically, phytochemicals that
have benefits on normal organ function via support of healthy mitochondria may counter cancer altering
mitohormesis.

Thus the working concept here, capitalizing on the precepts of hormesis, is that for phytochemicals to be
effective as chemopreventives at the earliest stages and continuously as guardians against tumorigenesis,
combinations must be sought that work within the low dose range permitting adaptive responses and
[77]
not toxicological responses . This would then provide the protection against biological stresses affecting
normal homeostasis of tissues and cells and that can intervene in tumorigenesis, whether genetic or
[84]
epigenetic. To paraphrase the summary statements in the review article on stress response by Zelenka et al.
they indicate the following. Upregulation of the cellular stress response pathways are governed by
exercise, natural compounds, or drugs that protect the body against carcinogenesis. However, the same
stress response pathways may protect cancer cells against metabolic and oxidative stress associated with
metastatic dissemination and anticancer therapy. In cancer prevention upregulating stress responses of the
body are desirable, but anticancer drugs that downregulate stress response in tumor cells have just emerged.
In targeting of the stress response, less specific multi-targeting approaches are often more successful than
those targeting a single molecular target. It is noteworthy in stress response research that the dose of the
stressor and the time to adaptation dramatically influence the outcome of each study.

Of relevance here is the paradox of hormesis with the low-dose beneficial effects of stressors, viewing
nearly all phytochemicals as stressors, but having an intrinsic high dose toxic effect. Thus combinations of
phytochemicals, if well selected, when operating at low doses could maintain a precious homeostatic state
supporting normal functions and the anti-neoplastic resistant state in all tissues and organs. Biological
systems are innately adaptive to stressors and respond ideally if phytochemicals are delivered with optimum
duration and exposure.

INFLAMMATION AS A CRITICAL TARGET OF THE CANCER PROCESS
There is consensus amongst most scientists and physicians that inflammation is a critical component
of many pathological processes. For example, Tsoupras et al. analyzing the driving force behind
[85]
cardiovascular disease identified systemic inflammation and not cholesterol as the culprit. Especially in
cancer disease progression the inflammatory microenvironment can drive the malignant phenotype . In
[86]
fact, any perturbation in normal homeostasis is announced to the immune regulatory system in the body
and invites inspection and reaction from a variety of immune cells orchestrated to attempt resolution.
In this way it is well recognized that local or systemic inflammation can play a major role in how the
[86]
cancerous process rolls out . In the oncogenic microenvironment, as a perturbation of normal tissue
homeostasis, inflammatory events figure early on in the pathologic process and exacerbate the damage by
humoral factors and through recruitment of immune cells . This is where the anti-inflammatory activity
[86]
of phytochemicals and especially ITCs has relevance.

The ITCs and other phytochemicals could have a major chemoprevention impact on the development
of cancer precursor lesions, whether as occurring in embryonal derived cancers, for example, Wilms
[74]
tumor [87,88] or on in situ precursor lesions well documented in adult cancers . Certainly, the incidence
[89]
of precursor lesions is significantly higher than the progression to frank cancer . The derivation of pre-
malignant lesions can be understood in the context of the theoretical bases of the two hit hypothesis,
initiation and promotion, and the current day elaboration in genetic and epigenetic terms [62,54] . Furthermore,
we now have a much greater understanding of tumor progression towards metastasis, whether incurred
locally or via circulating tumor cells [13,90] ; all should be amenable to dietary phytochemicals. Therefore