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

Figure 3. The cancer cell programs

or may not partially overlap. For example, miR-21 and miR-222 are involved in uncontrolled proliferation,
miR-130 and miR-126 are involved in tumor angiogenesis and miR-373 and miR-155 are involved both in
[38]
invasion and metastasis . The existence of specific cellular programs activated during the cancer process,
suggests the possibility that the transformations induced by cancer both at the level of the tissue where it
originally appears, and at distant sites where metastasis are formed, are not simple random by-products
of malignancy but represent a well orchestrated process of local and global “cancerization”. In this paper, I
argue that the metastatic phenotype is initiated and maintained by non-random CISPN developed at the
organismic level. The emergence of these CISPN may result mainly from the finely regulated secretion by
the tumors and their stroma of specific exosomes [42,43] . Exosomes have been involved in the communication
[44]
between the primary tumor and remote metastatic sites and, cancer cell-derived exosomes contain
miRNAs that may regulate all the systemic hallmarks of cancer described below. In spite of the presence
[45]
of RNase in blood, miRNAs survive due to their presence in exosomes . Both the nature of the proteins
expressed on the surface of exosomes and the exosomes cargo are non-random as demonstrated by the
work of David Lyden’s lab [46,47] . Recently his team analyzed the protein exosomes from plasma of patients
with five cancer types (breast, colorectal, lung, pancreatic, mesothelioma) and found that in cancer
patients, the circulating plasma exosomes proteins, derive not only from the tumor itself, but also from the
tumor environment, distant organs (i.e., liver) and the immune cells, this data supporting the “cancerized”
[43]
organism model .
CLINICAL IMPLICATIONS OF THE MODEL OF CANCER AS A MODIFIED CELLULAR

PROGRAM
The division, invasion and metastatic programs may be activated differently and in different order in
various cancer types, and this may explain the fact that cancers arising in different tissues have different
propensity to grow locally, to invade the surrounding stroma and to metastasize. This might be related to
distinct modified cellular programs present in Cancer Stem Cells (CSCs). CSCs by definition are a small
subpopulation of cells within tumors with capabilities of self-renewal, differentiation, and tumorigenicity
when transplanted into an animal host. When we think of CSC we mainly think of their ability to grow
and form colonies but CSCs present in different tissues may not be the same qualitatively, and even,
[48]
quantitatively . It is likely that due to these differences, programs for division, invasion and metastasis