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Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63 Page 7 of 31

are differently activated in different CSCs. Some CSCs may “instigate” or “educate” the stromal cells by
[49]
secreting signals that induce changes in these cells that facilitate local invasion of the tumor . Other
distinct population of stem cells, so called migrating cancer stem (MCS) cells, may be responsible for
[50]
metastasis as proposed originally by Brabletz . Recently, this population of tumor cells with MCS
[51]
properties was identified in a study conducted at Memorial Sloan Kettering Cancer Institute (MSKCI) .
Using a colorectal cancer mouse model, the MSKCI investigators found two distinct population of stem
cells: an adenoma forming stem cells population with oncogenic mutations and a L1CAM positive tumor-
propagating metastasis-initiating stem cells without oncogenic mutations .
[51]

A pervasive oncology dogma postulates that cancer develops in a linear way by initially growing locally,
then subsequently invading the tissue where they appear and, finally, if given enough time, in the majority
of cases, metastasize. Experimental data and clinical practice suggest that this assumption is incorrect. Some
cancers, like breast or prostate, for example, sometimes behave as benign tumors that do not invade locally
or metastasize and, maybe, this is why, the global, indiscriminately screening programs for breast and
prostate cancers, may lead to over treatment of some patients. Another example is sarcoma, where roughly
[51]
50% of the sarcoma metastasize and 50% do not . As demonstrated by the work of Ganesh et al. , the
[52]
[53]
classical step by step genetic model of colorectal carcinogenesis of Fearon and Vogelstein may not apply
to the metastatic process who does not involve a specific set of mutated genes. The different activation of
different cancer cells programs in tumors of different types might explain the striking difference in clinical
stage presentations of different cancer locations. For example, as many as 55% of squamous head and neck
[54]
cancer presents as stage 4 most frequently with lymph nodes metastasis , but only approximately 7% of
thyroid cancers present as stage 4 . The presence of distinct cellular programs in cancer may also solve
[55]
the enigma of the existence of carcinomas of unknown origin where the primary tumor is never found. It is
conceivable that in metastasis of cancers of unknown origin the metastatic program is activated before the
division and invasive programs.

THE SYSTEMIC HALLMARKS OF CANCER
The hallmarks of cancer described by Hanahan and Weinberg in their two articles [18,19] , refer mainly to
[56]
the cellular and tissular hallmarks of cancer. More recently , Welch and Hurst proposed four cancer
hallmarks specifically associated with the metastatic process: motility and invasion, colonization, plasticity
and modulation but these four hallmarks are practically identical with the succesive steps of the metastatic
process described more than a decade ago by Joao Massagué [20,21] and his collaborators. In this paper, we
describe six novel systemic cancer hallmarks, that appear as a result of the interaction between cancer and
the organism at the macroscopic level. The first systemic hallmark is the cancer system itself established
through the connections between the primary tumor, the bone marrow and the distal metastasis. The five
other systemic hallmarks are as following: the global inflammation, the immunity inhibition, the metabolic
changes leading to cachexia, the propensity to thrombosis, and the neuro-endocrine changes [Figure 4].

Each of these six hallmarks is established through a different CISPN. In the sections below, I will discuss
one by one, the six CISPN. The accompanying figures [Figures 5-10] are raw sketches illustrating the salient
components of the different CISPN. Apart from the nervous system, the connections between the CISPN
components are made through exosomes, cytokines and other soluble factors, represented by the dotted
lines.

The primary tumor-metastasis network
Clinically, it has been noticed for a long time that the primary tumor and the distal metastases are
interconnected and co-dependent. In some cases of renal cell cancer, for example, resecting the primary
[57]
tumor induces a regression in the distal metastasis . On the contrary, in several experimental models, as
shown by Folkman and his collaborators, resecting the primary tumor may accelerate the development of
metastasis [58,59] . Over the last two decades, it has been demonstrated also that besides this primary tumor-