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Page 22 of 31 Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63

parathyroid hormone - related protein and small cell carcinomas (SCC) of the lung typically produce
calcitonin, adrenocorticotropin (ACTH), or gastrin releasing peptide (GRP). In some case for example,
bombesin (BBS)-like neuropeptides secreted by SCC can act as autocrine growth factors [223] . Besides
the involvement of cathecolamines in cancer described before, several other hormones (i.e., estrogens,
androgens) are well known to promote cancer development and metastasis [224] . Also, the role of the thyroid
hormones in promoting the metastatic process has been recently described [225] . Other hormones, like
melatonin, for example, may inhibit cancer metastasis [226] . Patient with cancer have poor sleep and this
may influence melatonin secretion. In a recent study done breast cancer women serum melatonin levels
correlated significantly with self-reported sleep quality and psychometric profiles of depression [227] .

INTEROGATING THE SYSTEM: CANCER INDUCED SYSTEMIC PATHOLOGIC NETWORKS
In the recent years, liquid biopises and “omics” became useful tools of the developing field of precision
oncology. Through liquid biopsies and “omics” we can interogate the global characteristics of the tumor
itself, and obtain useful information that help us in the diagnostic, prognostic and treatment of cancer
patients. In the near future, of great importance will be the characterization of the different CISPN through
specific biomarkers designed to analyze the systemic cancer hallmarks. This information might be used to
refine the staging and prognostic of patients with metastatic cancer currently lumped indiscriminatively
under one large umbrella by the TNM staging and, also, design and monitor targeted interventions directed
specifically against key CISPN that behave as master regulators of the metastatic process. Circulating
[42]
miRNA present inside the exosomes are plausible CISPN master regulators . Exosomal proteins isolated
from plasma of cancer patients have been recently characterized not only as useful biomarkers associated
[43]
with several cancer types but also for dissecting different CISPN involvement in the malignant process .
Potential systemic biomarkers might be also found analysing metabolomics data. In order for a tumor
to develop and spread needs energy and, global metabolic reprogramming, might well be one of the key
systemic cancer hallmarks driving cancer from its emergence through its progression and metastasis.
The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale
collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and
prognosis [228] . Systemic metabolic changes in advanced cancers have been described in the past for several
tumor types [229,230] . The essential role of metabolism at the cellular level in controlling cancer hallmarks
was recently proven. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, a
group of researchers identified distinct metabolic expression subtypes in 27 cancer types based on mRNA
expression patterns of seven major metabolic processes (amino acid metabolism, carbohydrate metabolism,
integration of energy, lipid metabolism, nucleotide metabolism, tricarboxylic acid cycle and vitamin &
cofactor metabolism) [231] . The metabolic expression subtypes correlated with clinical outcomes: subtypes
with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated
with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. The
most interesting finding was that these metabolic subtypes were not related to specific genetic somatic
drivers but were intrinsically coupled with cancer hallmark pathways (i.e., angiogenesis, cell division,
etc.) and were modulated by highly recurrent master regulators across cancer types, ultimately leading to
consistent survival patterns. As a proof-of-concept in vitro experiment, the authors also demonstrated
that knockdown of two master regulators genes of carbohydrate metabolic subtypes (SNAI1 in a lung
cancer cell line or RUNX1 in a sarcoma cell line) significantly decreased the concentrations of intracellular
glucose. According to this model, the master metabolic regulators identified were key nodes with the
greatest influence on systems-level metabolic activities and targeting these metabolic master regulators may
inhibit tumor progression. Strikingly, all four master metabolism regulators genes identified in the 8 cancer
types with significantly worse survival rates due to upregulated carbohydrate metabolism, SNAI1, RUNX1,
RUNX2, and FOSL1 [231] , play also a key role in embryonal development and EMT [13,232,233] and might be also
master regulators of the metastatic cellular program [Figure 3].