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Page 2 of 11 Mizejewski. J Cancer Metastasis Treat 2019;5:35 I http://dx.doi.org/10.20517/2394-4722.2018.70
[1]
BC patients adds to their ultimate demise in both young and older women . However, there exists an innate
flaw in BC cell survival and metastasis regarding its dependence on the microenvironment that surrounds
[2]
the malignant tumor . This dependence presents a novel opportunity into an untapped therapeutic
potential for BC patients with metastatic disease. The BC tumor mass maintains an intimate relationship
with its microenvironment via a 2-way interchange of cross-talk and signaling communication cues between
[3]
the two entities; this establishes a network-dependent connection . When tumor growth outpaces its blood
and nutrient supplies, cells detach from the primary mass seeking out new fertile “nesting” grounds. The
process of cell detachment, migration, and dissemination is the hallmark of metastases with its widespread
cell dispersion throughout the body; this results in an increased lethality more than the primary BC tumor
[4]
itself. In 1889, Stephen Paget proposed a “seed and soil” hypothesis in which break-away tumor cells seek
out tissue/organ sites which are beneficial to resume new tumor growth in sites resembling their original
microenvironments. Thus, migratory tumor cells seek out secondary nurturing destinations in which tumor
cells grow unabated in distal target organs such as liver, lungs, bone marrow, and brain.

The tumor cells themselves first undergo an epithelial-to-mesenchymal transition that transforms the
[5]
cell’s phenotypic identity to adopt a migratory and invasive behavior . The dispersed migrating BC
cells are attracted toward distal organ/tissue destinations under the influence of chemoattractant signals
that determine their migratory gradient patterns and behavior. The chemotactic signals originate from a
subfamily of secreted cytokines termed chemokines, most notably the CXCL12 ligand together with its
cognate cell surface receptor, CXCR4. Such a 2-member complex is present on both tumor cells and stromal
cells. Together, this chemokine/receptor complex forms an axis that can regulate cancer cell growth,
[6]
proliferation, chemoresistance, angiogenesis, and metastasis . Hence, both the directive and the objective of
the present report are to address the cancer cell-to-microenvironment interaction as a potential therapeutic
intervention strategy targeted toward disrupting the communication signaling network both at primary
tumor and its metastatic sites.

THE TUMOR MICRO-ENVIRONMENT COMPONENTS
The micro-environment surrounding the primary tumor mass and that encompassing the metastatic
destination site have similar shared communication networks. The tumor cell-to-microenvironment
connection serves as a signaling bridge between tumor cells and interstitial stromal components which
sponsor two-way communication systems. Such signaling activities include nutrient supply, angiogenesis,
cell adhesion, migration, cell-to-cell contact, adherens cell junction maintenance, invasiveness, and
[7]
basement membrane proteolysis . Non-cellular constituents of the interstitium consists of multiple and
diverse components such as: (1) metabolic by-products; (2) exosomes and microvesicles; (3) cell secreted and
cell-surface proteins, co-factors and enzymes; (4) extracellular matrix components; (5) signaling molecules;
and (6) endocrine and exocrine secretions such as cytokines. The non-malignant cell populations residing
in the extracellular spaces and matrices consist of: (1) capillary and lymphatic cells of vessels and ducts; (2)
extracellular matrix (ECM) cells; (3) stromal cells; (4) mesenchymal stem cells; (5) fibroblasts; (6) pericytes;
(7) immune-associated cells (lymphocytes); (8) macrophages; (9) myofibroblasts; and (10) endothelial
cells [3,8,9] . Some of these constituent cells express and secrete various proteins involved in growth, cell
movements, apoptosis, membrane proteolysis, and integrin and growth factor signaling. Thus, the cellular
and non-cellular components of the instititual and ECM spaces represent an untapped source of potential
molecular and cellular targets for cancer therapy. These will be addressed below.

CELL SIGNALING IN THE MICROENVIRONMENT
The tumor-to-microenvironment intracellular spaces offer a little-recognized cluster of molecular
signaling targets with no place to hide. Hematologic and solid tumors are known to interact through
microenvironments via cell surface chemokine receptors and their cognate ligands. As discussed above, the