Page 341 - Read Online

Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63 Page 19 of 31

between anabolism and catabolism in the pancreas, leading to a concomitant release of catabolic glucagon
and anabolic insulin [177] . According to him, the first cells that manifest a hybrid metabolism are the
stem cells. Subsequently, this metabolic rewiring is stabilized through mutations or epigenetic changes
selecting the most aggressive population and cancer cells arise. In his model, the pancreatic alteration is
the primum movens of cancer followed by the metabolism switch of stem cells. The stem cells, initially
committed to repair an organ, subsequently transform into cancer cells that use their metabolic advantage
to compete for resources with the rest of the organism [177-179] . The practical value of Israël’s model is first the
prediction that cancer could be detected several years before its clinical manifestations because of specific
metabolome changes, and, second, the proposal of correcting the GABA switch pancreatic anomaly as a
method for cancer prevention. In 2016, a group of German researchers analyzing data from the European
Prospective Investigation into Cancer and Nutrition study found that abnormalities of two lipid metabolites
(high levels of phosphatidylcholine PC ae C30:0 and low levels of lysophosphatidylcholines, C18:0, were
consistently associated with increased risk of breast, prostate and colorectal cancer. These abnormalities
were detected several years before the clinical apparition of cancer pointing to a global metabolic shift in
phosphatidylcholine metabolism that may drive tumorigenesis [180] .

The thrombosis network
The role of different blood components [181] and the lymphatic system [182] in the metastatic process has been
coming more and more into focus. Therapies targeted against other blood and lymphatic factors involved
in cancer are in development [181,182] . As many as 20% of cancer patients may have a thrombosis event during
their lifetimes [183] . As shown in a recent review [184] , a reciprocal connection exists between cancer and
thrombosis, on one side cancer cells supporting clot formation, on the other side, clotting proteins support
cancer growth and dissemination. Cancer is associated with a state of hypercoagulability, driven in part
by the release of procoagulant factors, such as tissue factor (TF), released by the malignant tissue, as well
as by inflammation-driven activation of endothelial cells, platelets, and leukocytes. Also, cancer cells are
able to directly adhere to host cells (i.e., endothelial cells, monocytes, platelets, and neutrophils), thereby
stimulating additional prothrombotic properties of the host thrombosis effector cells [184] [Figure 9].

TF is considered to be the major molecular driver of cancer-associated coagulopathy and thromboembolic
disorders. It is expressed either by cancer cells or its expression is induced by cancer cells in normal
vascular tissues by both the release of soluble mediators and the direct cancer cell - host cell contact.
Its expression is related to well defined oncogenic events: epidermal-to-mesenchymal transformation,
TGF-β signaling, EGFR, phosphatase and tensin homolog (PTEN) and Src pathways, hypoxia induced
signaling, etc. The majority of human epithelial cancers (lung, colorectal, prostate, breast, pancreatic,
gastric, melanoma, etc.) are characterized by abundant levels of TF [185] . Also, as shown by a Canadian group
in a glioma model, TF may also control the state of tumor dormancy by recruiting to the tumor niche
myeloid and blood vessels forming cells [186] . Interestingly, the procoagulant and the signaling effect of TF in
tumor biology can be targeted separately, and there are therapies under investigation that target solely the
signaling effect of TF without affecting its homeostatic function [187] .

In addition, cancer cell interactions with platelets and neutrophils contribute to cancer cell adhesion,
extravasation, and the establishment of metastatic lesions [188] . Platelet-derived signals are required for the
rapid intravascular recruitment of neutrophils to circulating tumor cells (CTCs) thrombi contributing
to “early metastatic niches” [123] . Also, TGF-β secreted by degranulating platelets may contribute to the
activation the NF-κB pathway in carcinoma cells, thereby inducing or sustaining the expression of EMT
programs in the CTCs [189] . Selectins are carbohydrate-binding molecules that bind to glycan structures,
present on endothelial cells, platelets and leukocytes. There are three members of the selectin family:
P-selectin expressed on activated platelets and endothelial cells, L-selectin present on leukocytes and
E-selectin expressed on activated endothelial cells [190] . P-selectin in particular seems to play a crucial role in