Abstract
Hypoxia, a common feature of solid tumors, has been critically involved in cell invasion and metastasis, but the underlying mechanisms remain poorly understood. Previously, it has been observed that the lysophosphatidic acid receptor 4 (LPA4) signaling axis mediates production of the degradative subcellular structures invadopodia, which are known to be required for metastasis. Here, it is demonstrated that LPA1 (LPAR1) is a common and major receptor used for hypoxia-induced invadopodia production in various cancer cell lines. The widespread use of LPA1 was not due to increased LPA1 expression but rather relied on Src-mediated cross-talk with EGFR. LPA1-mediated phosphorylation of Y845-EGFR under hypoxia led to PI3K/Akt activation, an event that increases the ability of cells to produce invadopodia. Moreover, phospho-Y845-EGFR was upregulated in hypoxic zones of tumors and a combination of EGFR and LPA1 inhibition synergistically suppressed metastasis in vivo Implications: This study uncovers an LPA1-EGFR signaling axis that is used for cell invasion in hypoxia and suggests a potential target to impede cancer metastasis. Mol Cancer Res; 16(10); 1601-13. ©2018 AACR.
Highlights
Metastasis is the leading cause of mortality in cancer patients
We have previously reported that lysophosphatidic acid receptor 4 (LPA4) signaling was involved in invadopodia production in HT1080 cancer cells cultured under normoxic conditions [11]
Because LPARs can have cell type– and context-dependent effects on cell motility and invasion [19], and because several G-protein–coupled receptors (GPCR) are known to play a role in hypoxiamediated signaling [20], we sought to investigate which LPAR and downstream signaling were involved in invadopodia formation under hypoxic conditions
Summary
Metastasis is the leading cause of mortality in cancer patients. effective therapies targeting the disseminated disease remain a major challenge in clinical management of the disease. The tumor microenvironment is increasingly recognized to play a significant role in many of the hallmarks of cancer, notably as an important modulator of tumor cell phenotypes driving cell invasion and metastasis [1]. It has been recently reported that tumor microenvironment stimuli such as hypoxia and the associated acidic pH induce cell invasion and metastasis through activation of sodium–hydrogen exchangers, growth factors, metalloproteases, or RhoGEFs [4]. In these reports, the increase in cellular invasion was associated with production of invadopodia, which are specialized cell structures required for cancer cell dissemination
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
