Table II.

Targeting molecular mechanisms that enable soluble communication.

Target	Molecular Mechanism	Reference
TGFβ	TGFβ ligands (a 40-member superfamily that incudes TGFβ1, 2, and 3) control cellular growth, differentiation, and motility through heteromeric signaling complexes composed of the TGFβ type I, II, and III receptors. Neutralizing antibodies can diminish metastasis.	[108–111]
VEGF	Ligands that belong to the VEGF-PDGF super family where the VEGF gene yields five isoforms (A–D) that bind to four receptors (Flt-1, Flk-1, neuropilin-1, and Flt-4).	[180–182]
EGF	The EGF family includes ten ligands that bind to dimeric ERBB receptors to induce pro-migratory signaling via receptor tyrosine kinase activity. Currently a target of many anti-cancer therapeutics, EGF receptor is upregulated in many cancers (breast, colorectal, lung).	[33, 112–114]
SDF-1	A soluble cytokine that binds to its cognate receptor CXCR4. First recognized for its broad impact on immune functions and ability to control homing of bone marrow cells, it is also involved in the homing of tumor cells to distant sites.	[177–179]
TNFα	The most studied member of the tumor necrosis family of cytokines first recognized as a regulator of the immune response. It is produced by a large number of human tumors. The highest levels of TNF-α is secreted by foreign leukocytes present in the tumor microenvironment. Plays a dual role as about both a tumor suppressor and tumor promoter. High serum expression in patients is associated with a poor prognosis.	[68, 115, 116]

Molecules included here are representative molecular determinants of the underlying principle