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Page 20 of 31 Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63

several types of cancer metastasis by mediating the aggregation of platelets with tumor cells forming clots.
A recent study showed that intravenous injection of melanoma cells into WT mice resulted in multiple lung
metastases, while in P-selectin-deficient mice pulmonary tumor metastasis and trapping of tumor cells in
the lung was significantly reduced [191] . Modulating the interaction between cancer cells and the circulating
blood cells, and respectively, between cancer cells and the endothelial cells may represent novel therapeutic
approaches. For example, there is experimental evidence that targeting specific types of the integrin
receptors present on the surface of the platelets efficiently reduces tumor cell colonization into the lungs,
suggesting that they could represent interesting targets for anti-metastatic drugs [192] .

A team from France characterized the microparticulosome, the repertoire of plasma membrane vesicles
produced by different types of cells and was able to differentiate a microparticle signature associated
with pancreatic and colorectal cancer [193] . The same team showed in syngeneic ectopic and orthotopic
mice models that treatment with the drug Clopidogrel prevented the binding of cancer cell‐derived
microparticles to fibrinogen‐platelets aggregates at the site of thrombosis, and reduced the metastasis and
the extent of thrombosis associated with cancer [194] . Procoagulant factors associated with exosomes from
tumors have been described for almost four decades [195] Tissue factor associated with exosomes has been
found to be responsible for the Trousseau syndrome in one patient with lung cancer [196] and there are
several studies documenting the procoagulant effect of tumor exosomes [197] .

The neuro-endocrine network
Both the central nervous system and the neurovegetative nervous system are intimately involved in cancer.
One of the most studied links between central nervous system and cancer is stress. The neuroendocrine
mediators reach the cells of the immune system either through the peripheral circulation or through direct
innervation of lymphoid organs [Figure 10]. As suggested by Claire Magnon [198] , a possible explanation
for tumor formation associated with stress might rely on the activation of the sympathetic nervous system
(SNS) through the sympathetic - adrenal - medullary axis, which controls the release of adrenergic
neurotransmitters such as epinephrine or norepinephrine by the adrenals into the bloodstream in support
of the fight-or-flight reflex. Catecholamine-mediated suppression of cellular immunity may play a role
in increased growth of certain tumors [199] . Also, primary and secondary lymphoid organs are innervated
by sympathetic nerve fibers. Lymphocytes and monocytes express receptors for several stress hormones,
including CRH, adrenocorticotropic hormone (ACTH), cortisol, norepinephrine, and epinephrine.
Therefore, it is possible that the neuroendocrine hormones released during a stressful event could alter
immune function and subsequently alter the course of immune-based diseases [200] . It has been reported
that mice living in an enriched housing environment (EE) show reduced tumor growth and increased
remission [201] . This effect was described in melanoma and colon cancer models, and, it was proven that
it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE)
inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain derived
neurotrophic factor (BDNF) was selectively upregulated by EE, its genetic overexpression reduced tumor
burden, whereas BDNF knockdown blocked the effect of EE. The hypothalamic BDNF downregulated
leptin production in adipocytes via sympathoneural β-adrenergic signaling [201] .

A key central nervous system structure involved in cancer is the hypothalamus. In the context of
systemic inflammation, the hypothalamus integrates signals from peripheral systems, translating them
into neuroendocrine perturbations, altered neuronal signaling, and global metabolic derangements [202] .
Cytokines, like IL-1β and TNF-α, for example, generated in the periphery during cancer progression are
amplified and modified within the hypothalamus, leading to hypothalamic inflammation and aberrant
activity of weight- and activity-modulating neurons that may induce muscle atrophy via activation of the
hypothalamic-pituitary-adrenal axis [203,204] . Hypothalamic inflammation may be followed by dysregulation
of homeostatic regulation of autonomic nerves (innervation of muscles, liver, fat tissue, endocrine glands