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Mizejewski. J Cancer Metastasis Treat 2019;5:35 I http://dx.doi.org/10.20517/2394-4722.2018.70 Page 3 of 11

major components in the extracellular signaling arena are the chemokine receptor complexes present on
both tumor and ECM cells, which activate diverse intracellular signaling transduction events as discussed
[10]
above . Such intracellular signaling systems can activate a variety of pathways such as ERK1/2, p38, JAC/
[11]
STAT, SAPK/JNK, NF-κB, mTOR, PI3K-AKT, and BT-kinases . Chemokine receptors, such as CXCR4
and CXCR7, represent members of the seven-transmembrane domain G-protein coupled receptor family
that transmit intracellular activation of processes such as calcium flux, chemotaxis, transcription, cell cycle
[13]
transition, and cell survival . The disruption, blockage, or dysregulation of chemokine receptors and
associated proteins could lead to aberrant off-target signaling and de-sensitization of the chemokine receptor
transactivation apparatus.

At present, the increasing insight and appreciation of the functional role of the microenvironment to cancer
growth and metastasis is prompting further research to more fully elucidate and investigate the tumor cell-
to-stoma cell dependency. The identification of metastasis-associated protein targets, both cell-bound and
secreted, which occupy the extra-cellular matrix and spaces are key targets for disabling the communication
lines between the tumor and the interstitium. The protein constituents which aid and abet this signaling
complex display properties associated with processes such as cell adherence, cell-to-cell contact,
invasion, immigration, matrix proteolysis, growth factor and receptor regulation, and ECM remodeling
and restructuring. For example, a recent report has described the existence of a cancer cell-to-stromal
macrophage EGF/CSF-1 paracrine signaling loop in the invasive spread of a primary rat mammary tumor
[Figure 1]. The invasive response was inhibited by blocking the EGF and CSF receptors and/or macrophage
function demonstrating that tumor migration invasiveness was dependent on the paracrine loop.

PROTEIN CONSTITUENTS OF THE TUMOR MICRO-ENVIRONMENT
The intrinsic pressure driving the metastatic process of tumor cells is the need for additional nurturing
factors such as new blood vasculature and increased nutrients for the ever-expanding volume of the primary
tumor cell mass. The disseminated tumor cells take advantage of the metastasis-associated proteins already
residing in and on the cells of the ECM and interstitial spaces. These metastasis-associated proteins, so
crucial for break-away tumor cells, are presented in the discourse listed below and in Table 1.

Cell adherence and cell-to-cell contact family proteins
Cell adherence and contact processes can be attributed to a gene superfamily termed the cadherins which
[14]
consist of protocadherins, cadherins, desmocollins, desmogleins, contactins, and connexins [Table 1].
Such proteins function in cell adhesion to other cells, and to ECM constituents, and to formation of adherin
2+
junctions between cells. Cadherin family members display calcium (Ca ) binding repeat domains in their
[15]
intrinsic polypeptide structure . Different cadherin subfamily members can act in concert to join cells
together in both homotypic and heterotypic types of attachments. Some family members (protocadherin
Cad-13) serve to stabilize and maintain cell connections during oxidative stress, neural cell development,
[16]
neurite outgrowth, cell signaling, invasion, and migration . Other family members are involved in
cell survival, potassium channel transmission, maintaining the microvasculature, KRAS signaling, and
transmembrane activities. The PECAM, connexin, and contactin proteins play roles in gap junction
[17]
maintenance, platelet adherence, and aged white blood cell removal and destruction .

ECM family proteins
The ECM family of proteins include the integrins, zinc matrix metalloproteases (MMPs), A distingrin and
[18]
metalloproteinase (ADAM) family, collagenases, gelatinases, and annexins [Table 1]. The MMPs are
synthesized as nonactive precursor proteins which require proteolytic cleavage exposing catalytic hemopexin
domains utilized for collagen degradation. The MMPs play key roles in development, metabolic disorders
and diseases, immune and autoimmune disorders, and in cancer. In comparison, the ADAM family
members function as transmembrane-anchored proteins resembling snake venom disintegrins which are