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This KEGG map shows how sugar-coated proteins on the cell surface and in the surrounding matrix (proteoglycans such as syndecans, glypicans, CD44 and decorin) catch growth factors and hand signals to receptors. It matters because these molecules set how loudly growth signals reach the tumour cell and how easily it invades.
Proteoglycans are core proteins carrying long sulphated sugar chains (heparan sulphate, chondroitin sulphate, dermatan sulphate or keratan sulphate); hyaluronan is the related free sugar polymer. KEGG map hsa05205 draws how these molecules in the tumour microenvironment feed proliferation, adhesion, angiogenesis and metastasis. Hyaluronan binding to CD44 promotes growth and migration. Cell-surface heparan sulphate proteoglycans, the syndecans (1 to 4) and glypicans (1 and 3), bind growth factors, cytokines and morphogens through their heparan sulphate chains and present them to receptors such as FGFR, EGFR, IGF1R, MET and VEGFR, driving RAS-ERK, PI3K-AKT, Wnt and Hedgehog signalling. Perlecan in the basement membrane does the same for angiogenic factors. In contrast the small leucine-rich proteoglycans decorin and lumican act as tumour repressors: decorin binds EGFR and MET and dampens their signalling.
Iozzo and Sanderson, Journal of Cellular and Molecular Medicine, 2011 (doi:10.1111/j.1582-4934.2010.01236.x) review this biology and stress two enzymes that remodel the system: heparanase, which clips heparan sulphate and releases bound growth factors, and the sheddases that release syndecan-1 from the cell surface, both linked to invasive and angiogenic behaviour in myeloma and solid tumours.
What can be done: the proteoglycans themselves are mostly targeted indirectly. Glypican-3, which is expressed on most hepatocellular carcinomas and almost no normal adult tissue, is an antibody and CAR-T antigen. The receptor tyrosine kinases that proteoglycans co-activate are druggable with FGFR inhibitors (pemigatinib, futibatinib, erdafitinib), EGFR inhibitors and MET inhibitors, and the downstream Hedgehog route with vismodegib, which KEGG lists against this map. Heparan sulphate mimetics such as necuparanib, also listed by KEGG, have been tested in early trials.
Picture the space around a cell as a sticky sugar lawn. Growth-factor messages land on the lawn and cling to it, and the proteoglycans act like ushers that pick messages up and walk them to the receptor doors. Some ushers (syndecans, glypicans) shout the message louder; a few (decorin) quietly bin it. Cancer hires more of the loud ushers and sends in gardeners (heparanase) that cut the lawn so trapped messages fly free.
Shares FGF / FGFR signalling, Ramucirumab, Epithelial-mesenchymal transition & drug efflux, FGFR2.
Shares Erdafitinib, Futibatinib, FGF / FGFR signalling, Pemigatinib.
Shares HGF, Savolitinib, VEGF angiogenesis, PI3K / AKT / mTOR.
Shares Erdafitinib, FGF / FGFR signalling, VEGF angiogenesis, Epithelial-mesenchymal transition & drug efflux.
Shares Futibatinib, Pemigatinib, FGFR2.
Shares VEGF angiogenesis, Ramucirumab, Wnt / β-catenin, PIK3CA / PI3K-alpha.
Shares Smoothened (hedgehog pathway), Vismodegib, Hedgehog signalling.
Shares Futibatinib, Pemigatinib, FGFR2.