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Page 12 of 31 Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63

immunosuppression, organotropism and reprogramming. These characteristics determine whether
the metastatic cells present in the blood circulation can colonize and survive or become dormant after
[69]
arrival . The best well described tumor secreted soluble molecules responsible for the niche formation
[69]
and development are: VEGF-A, placental growth factor, and versican . Besides the cancer cells, there
are also factors secreted by the tumor stroma that play a similar role: TGF-β, TNF-α, hypoxia-inducible
factor-1 (HIF-1), granulocyte colony-stimulating factor (G-CSF). Some of these factors are secreted by the
BDMCs themselves: VLA-4 (integrin α4β1), matrix metalloproteinase (MMP)9 and ID3 protein (ID is a
term that refers to its functional properties as both an inhibitor of DNA binding and an inhibitor of cell
[70]
differentiation) .

The exosomes are key factors responsible for the preparation of the pre-metastatic niche and the
communication between the tumor, the bone marrow and the distal metastatic site [41,71] . Different materials
(proteins, mRNAs, DNA and miRNAs) carried inside the exosomes can be functionally delivered between
different types of cells and transferred to distant locations, influencing the biological activities of tumor and
non-tumor cells and promoting tumor growth, invasion, metastasis, angiogenesis, and drug resistance [42,71] .
A comprehensive review highlighted the key role played by the ECM components like syndecan in
[72]
regulating exosome biogenesis, protein composition, function, and docking to recipient cells . Heparan
sulphate chains of syndecans are essential for exosome formation within endosomal compartments, and
trimming of heparan sulphate by heparanase activates the formation of an endosomal complex containing
[73]
syndecan coupled to syntenin and ALIX . Reversely, tumor exosomes expressing high CD44 expression
bind to hyaluronic acid and modulate the ECM as demonstrated for degradation of collagens, laminins,
[74]
and fibronectin . Tumor-associated exosomes have been identified in biological (plasma, urine, saliva)
and pathological (malignant effusions, pleural effusions, ascites) fluids from cancer patients. David
Lyden’s team from Weill Cornell Medical Center (WCMC), was able to demonstrate that in melanoma
the transfer of the MET oncoprotein from tumor-derived exosomes to BM progenitor cells promoted the
metastatic process and to describe quantitative and qualitative exosome signatures, along with specific
[75]
BM progenitor cell populations mobilized as representative hallmarks of metastatic disease . Certain
miRNAs are enriched in exosomes coming from the cancer cells, indicating that the exosomes composition
[76]
seems to be controlled . Exosomes from mutant KRAS colorectal cancer cells for example show a distinct
[77]
miRNA profile compared to wild type cells . The same WCMC team showed that in pancreatic cancer,
the exosomes contained macrophage inhibitory factor (MIF) that is involved in the recruitment of bone
marrow-derived macrophages and the blockade of MIF prevented liver pre-metastatic niche formation
and metastasis. By releasing soluble factors, tumor cells were able to specifically direct bone marrow
[68]
derived cells to the sites were they were supposed to go . An “integrin code” present on the surface of
the exosomes seems to be responsible for the homing of future metastasis to precise prespecified distal
[46]
organs .
Redig and McAllister also included the participation of the bone marrow as a sine qua non component
[78]
of the “instigation” model . These authors demonstrated a process of “systemic instigation” by injecting
cells coming from an aggressive breast tumor in the flank of a mouse and analyzing the effect of these
cells on the growth in the opposite flank of tumor cells coming from an indolent breast cancer tumor. The
explanation for the influence at distance of one cancer tissue on the growth of another was established to
be bone marrow-derived cells that were recruited to the distal sites and instigated the previously indolent
tumor cells to grow . The importance of studying cancer as a systemic disease was underscored by another
[78]
[79]
study done by a group of researchers from Harvard Medical School . The authors described a systemic
cross-talk between lung tumors and bones. In an elegant mouse model, lung adenocarcinomas were able
to remotely activate osteoblasts in bones even in the absence of local metastasis. In turn, these osteoblasts
supplied tumors with neutrophils, which fostered cancer progression .
[79]
Sometimes, the initiators of this “trialogue” are not the tumor cells themselves, but other stromal cells
derived from the “cancerized” stroma. Cancer-associated fibroblasts have been shown, for example, to