Extracellular ATP and Macropinocytosis: Their Interactive and Mutually Supportive Roles in Cell Growth, Drug Resistance, and EMT in Cancer.

Macropinocytosis is one of the major mechanisms by which cancer cells uptake extracellular nutrients from tumor microenvironment (TME) and plays very important roles in various steps of tumorigenesis. We previously reported the unexpected finding that intratumoral and extracellular ATP (eATP), as one of the major drastically upregulated extracellular nutrients and messengers in tumors, is taken up by cancer cells through macropinocytosis in large quantities and significantly contributing to cancer cell growth, survival, and increased resistance to chemo and target drugs. Inhibition of macropinocytosis substantially reduced eATP uptake by cancer cells and slowed down tumor growth in vivo. More recently, we have found the eATP also plays a very important role in inducing epithelial-to-mesenchymal transition (EMT), and that macropinocytosis is an essential facilitator in the induction. Thus, macropinocytosis and eATP, working in coordination, appear to play some previously unrecognized but very important roles in EMT and metastasis. As a result, they are likely to be interactive and communicative with each other, regulating each other's activity for various needs of host tumor cells. They are also likely to be an integral part of the future new anticancer therapeutic strategies. Moreover, it is undoubted that we have not identified all the important activities coordinated by ATP and macropinocytosis. This review describes our findings in how eATP and macropinocytosis work together to promote cancer cell growth, resistance, and EMT. We also list scientific challenges facing eATP research and propose to target macropinocytosis and eATP to reduce drug resistance and slow down metastasis.