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

Table 1. Selected metastasis-associated protein constituents of the tumor microenvironment are listed as four major
functional groups. Such proteins are involved in cell activities such as adherence, mobility, growth, migration, invasiveness,
angiogenesis, signaling, and proteolytic degradation
Group-I proteins: cell adherence and cell-to-cell contact
1. Protocadherin-Beta-1 (Q9Y5F3)
2. Cadherin-6 (AAH00019)
3. Cadherin-13 (NP_001248)
4. Cadherin-22 (CAB51587)
5. Contactin-3 (N_P387504)
6. Neural Cell Adhesion Molecule (NP_000606)
7. Platelet Endothelial Adhesion Molecule (NP_000433)
8. Connexin GJA5 (AAH13313)
9. Neuratropic tyrosine kinase R-3 (NP_001012338
Group-II proteins: matrix metalloproteases (MMP) and ADAMS
1. MMP-2 (ABD38929)
2. MMP-9 (CAC10459)
3. MMP-10 (AAH02591)
4. MMP-13 (AAH74808)
5. ADAM-22 (NP_068368)
6. Integrin Alpha-6 (AAH50585)
7. Integrin Alpha-2 (NP_002194)
8. Annexin-A8 (P13928)
9. Collagen IV, Alpha-3 (CAA56335)
Group-III proteins: growth factor receptors - cell surface
1. Fibroblast Growth Factor Receptor (P22455)
2. G-protein Coupled Receptor-54 (QT69F8)
3. Interleukin-8 Receptor (NP_001548)
4. FMS-like Tyrosine Kinase Receptor (AAB23636)
5. Laminin Receptor (AAC50652)
6. TSH-associated Receptor (AAD31568)
7. Somatostatin Receptor-2 (NP_001041)
8. Ephrin Receptor-2B (CA122899)
9. C-Met Hepatocyte Growth Factor Receptor (NP_000236)
Group-IV proteins: growth factors and regulators
1. Transforming Growth Factor B-1 (NP_000651)
2. Vascular Endothelial Growth Factor (CAC19516)
3. Retinoblastoma-Assoc. Protein-1 (NP_000312)
4. p53 Protein Tumor Cell Antigen (NP_000537)
5. Tyrosine Protein Phosphatase Non-Receptor-7 (NP_002823)
6. C-terminal (CTB) Binding Protein (AAD14597)
7. NME-Nucleoside-Disphosphate Kinase (CAG46912)
8. Metastasis Suppressor Protein MTSS-1 (AAF15947)

See Table 3 for Metastasis-associated functional activities, text, and Ref.[14-31]. Parenthesis indicates National Center for Bioinformatics
(NCBI) Accession number. ADAM: A disintegrin and metalloproteinase gene family

[24]
growth factor, laminin, somatostatin, ephrin, IL-8, and KISSIR . The receptor-mediated activities
encompass angiogenesis, mitogenesis, growth enhancement, differentiation, kinase function, cancer
genesis and maintenance. These receptors can further activate, influence, and regulate cell cycle transitions,
mitogenesis, cell motility, migration, and metastasis. Some receptors contain tyrosine kinase domains
that enhance or influence growth in multiple tissues including the blood vasculature. The somatostatin
receptors regulate the release of various hormone and secreted proteins, while the ephrin receptors are
involved in tissue formation, cell migration and contact, stem cell differentiation, and cancer growth [25,26] .
Finally, the G-coupled receptor-54 functions as a receptor for the KISS gene product, a cancer metastatic
suppressor protein which when mutated, induces chemotaxis and invasion in numerous cancer cells. Thus,
the metastasis-associated growth factor receptors are heavily involved in cell-to-ECM adhesion, invasion,
migration, cancer growth and metastatic activities.

Growth factor and regulator family members
The microenvironment and metastasis-associated proteins encompass a wide range of growth factors and
kinase enzymes that include transforming growth factor, vascular endothelial growth factor, MTSS1, p53 cell