Several of the growth factors and their receptor tyrosine kinases (RTK) such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and insulin are promising candidate targets for cancer therapy. Indeed, tyrosine kinase inhibitors (TKI) have been developed to target these growth factors and their receptors, and have demonstrated dramatic initial responses in cancer therapy. Yet, most patients ultimately develop TKI drug resistance and relapse. It is essential in the clinical setting that the targeted therapies are to circumvent multistage tumorigenesis, including genetic mutations at the different growth factor receptors, tumor neovascularization, chemoresistance of tumors, immune-mediated tumorigenesis and the development of tissue invasion and metastasis. Here, we identify a novel receptor signaling platform linked to EGF, NGF, insulin and TOLL-like receptor (TLR) activations, all of which are known to play major roles in tumorigenesis. The importance of these findings signify an innovative and promising entirely new targeted therapy for cancer. The role of mammalian neuraminidase-1 (Neu1) in complex with matrix metalloproteinase-9 and G protein-coupled receptor tethered to RTKs and TLRs is identified as a major target in multistage tumorigenesis. Evidence exposing the link connecting growth factor-binding and immune-mediated tumorigenesis to this novel receptor-signaling paradigm will be reviewed in its current relationship to cancer.