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form even when the tumor appears localized. This may be the reason why even when detected very early, a
significant proportion of cancers is incurable. For example, the 5 year survival of stage I non-small cell lung
cancer disease is approximately 60% (American Cancer Society Statistics, 2020). In 2019, a neuroscientist,
[8,9]
Jeremy Borniger, published two papers focused on brain-tumor interactions, with special emphasis on
the interaction of subcortical neural populations and cancer. Specifically, he and his team discovered that
non-metastatic breast tumors may influence the endocrine and the immune systems of the hosts. Using a
breast cancer mouse model, they demonstrated that by inhibiting the signaling of the lateral hypothalamic
orexin/hypocretin neurons, the sleep quality and the metabolic dysregulations induced by the tumor were
[9]
improved .

We have also proposed previously the need for a broader, systemic perspective on cancer and introduced
[10]
briefly the idea of the cancer system . The notion of the cancer system although closely related to the
idea of the cancer-systemic disease is different in a fundamental way. The meaning of the word “systemic”
refers to “affecting the body generally”. Metastatic and, sometimes, localized cancers, influence the whole
organism and therefore they are classified as systemic diseases. On the other hand, macroscopically, cancer
behaves like a sort of an organism within an organism and metastasis appears as a finely orchestrated
process. The concept of a cancer system tries to capture precisely this deterministic behavior.

Cancer as a developmental disease
The idea that cancer represents an embryonal developmental program gone haywire has been around for
[13]
more than four decades [11,12] . As shown by a recent review there are some tissular and organismic genes
that may play a role both in embryogenesis and cancer. It is important to point out that until approximately
three weeks after fertilization, the embryo does not have a functioning circulatory system, and, therefore,
the developmental programs involved in the embyo development are likely different from that of the
metastatic process. A notable exception is the neural crest migration where epithelial-to-mesenchymal
transition plays a critical role. Similar to the neural crest migration , the metastatic process represents
[14]
a transformed cellular program that once activated leads to the development of disseminated tumors at
distance from the original site. The fact that that the same genes (i.e., the nuclear hormone receptors,
Hedgehog, Wnt, TGF-β, Notch) are involved in the generation and maintenance of multicellularity, and,
they are also dysregulated in stem cells and metastasis , suggest the striking idea that cancer, in general,
[15]
and the metastatic process, in particular, may represent the activation of a developmental program
that leads to the creation of a novel, pervasive, multicellular entity. As previously suggested by Mark
Vincent, cancer appears to be much more than a simple dysregulated growth and may represent a form
of multicellular life, with symbiotic properties [16,17] , that establishes a commensual relationship with the
organism where it develops. In this process, the whole organism, “cancerized” through the development
of CISPN, as we will argue in this paper, far from being a passive bystander, becomes an active enabler of
cancer progression and spread.

Metastasis as a finely orchestrated deterministic process
As opposed to the apparition of malignant tumors that is, in general, related to genetic mutations,
metastasis appears to be mainly an epigenetic process. In the 2011 updated version of their original
hallmarks article , Hannahan and Weinberg, noted that the ability of cancer cells to invade and
[18]
metastasize may not require additional genetic mutations in addition to those already present in the
[19]
primary tumors . Also, the majority of the genes proposed by Massagué and collaborators more than a
[22]
decade ago [20,21] in their step by step model of metastasis are not mutated. In addition, Vogelstein et al.
noted that despite considerable effort, specific genetic alterations that distinguish cancers that metastasize
from cancers that do not metastasize have not been yet identified. The immediate conclusion, drawn by the
[22]
Vogelstein team , is that there are no specific metastasis genes.