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Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63 Page 5 of 31

This opinion of metastasis as a random, nondeterministic process has been challenged for 130 years since
Paget asked the famous question: “What is what decides what organs suffer from disseminated cancer?” and
[23]
launched the “seed and soil” hypothesis . By the late 70’s, metastasis started to be understood more and
[24]
more as the result of non-random tumor-host interactions , and the Paget’s “seed and soil” hypothesis has
[25]
[26]
been strongly supported by the work of Fidler and Kripke and Price et al. . A recent study described
widespread epigenetic reprogramming during the evolution of distant metastasis of pancreatic cancer
[27]
in the absence of metastasis-specific driver mutations . This manifested as global reprogramming of
histone H3K9 and DNA methylation within large heterochromatin domains (LOCKs) as well as regional
changes in gene regulatory modifications. Interestingly, the authors found that the epigenetic changes
were controlled by an anabolic glucose metabolism enzyme 6-phosphogluconate dehydrogenase (PGD).
Glucose deprivation, RNA interference (RNAi) against PGD, and, treatment with 6-aminonicotinamide,
reprogrammed the chromatin state of the distant metastasis. In addition, cells treated with RNAi against
[27]
[28]
PGD did not form distal metastasis . Another recent study , found also that in prostate cancer the
master regulator genes of metastasis are genes involved in epigenetic regulation. Silencing a particular
histone methyltyransferase gene (Nuclear receptor binding SET Domain protein 2, NSD2) in vivo allografts,
resulted in significant improvement in survival in the mice treated as well as a significant reduction in the
[28]
metastatic burden without any effect on the primary tumor growth .
These observations suggest a different view of metastasis. The plethora of genetic abnormalities present in
established malignant tumors may not be the main driver of metastasis. No genetic mutation or mutations
[29]
have been unequivocally shown to be associated with progression from localized to metastatic disease .
As shown by several in vitro experiments, epigenetic factors present inside and outside tumor cells may
control the metastatic process. The cytoplasm of human embryonic stem cells can epigenetically reprogram
[30]
multipotent metastatic melanoma cells and made them to assume a melanocyte-like phenotype . Adam
Telerman and Robert Amson, two researchers from École Normale Supérieure from Paris, France, who
[31]
have been modeling tumor reversion for more than 20 years, stated that the “reversion process involves a
reprogramming mechanism using epigenetic and probably genetic tools that will supersede the changes in
cancer by assembling and triggering alternative ways leading to the suppression of tumorigenicity”. Some
of the metastasis master regulators may not be even located inside the cancer cell. The work of Bissell and
[32]
[33]
Radisky and Orimo and Weinberg demonstrated the crucial role of the tumor associated stroma in
[34]
promoting tumor metastasis. Convincingly, a recent review illustrated how hyaluronan, an integrated
component of the extracellular matrix (ECM), may modulate several key hallmarks of cancer: sustaining
of the proliferative signaling, evasion of apoptosis, angiogenesis, activation of invasion and metastasis,
reprogramming of energy metabolism and evasion of the immune response.

CANCER CELL PROGRAMS
If cancer cells switch back and forth between different programs, cancer may represent a controllable
cellular state that can rerouted to a non-neoplastic phenotype. The model of cancer as a potentially
reversible cellular program complements and refines the genetic model. It has been previously suggested
[35]
that many of the properties associated with invasion and metastasis do not arise as purely cell autonomous
processes . In most of the cases, the metastatic process seems to be due to adaptation and not to selection
[36]
[37]
of the cancer cells . It is the secretion of factors such as TGF-β, HGF, tumor necrosis factor (TNF)-α,
Wnt and PDGF by the surrounding tumor stroma, and, the activation in the tumor cells of several master
regulators of embryogenesis, such as the transcription factors Twist, Snail, Slug, Zeb1 and Zeb2, regarded
as the epithelial to mesenchymal transition (EMT) core regulators, that drive metastasis [13,29] . These
[38]
processes may be mediated by miRNAs , that coordinate multiple genes at the same time, so it will be
more appropriate to talk in terms of various cellular programs, i.e., a division program possibly controlling
[39]
key mitotic genes , an invasion program possibly controlling key invasion genes [40,41] , and, a metastatic
program, possibly controlling key EMT genes [Figure 3]. The master regulators of these programs may
[13]