The ability of
cancer cells to invade and metastasize is the major cause of death in
cancer patients. Autotaxin (ATX) is a secreted
lysophospholipase whose level of expression within
tumors correlates strongly with their aggressiveness and invasiveness. ATX is the major
enzyme involved in the production of
lysophosphatidic acid (LPA), a
phospholipid that is known to act mostly through its three first characterized
receptors (LPA(1), LPA(2), and LPA(3)).
Tumor cell invasion across tissue boundaries and
metastasis are dependent on the capacity of invasive
cancer cells to breach the basement membrane. This process can be initiated by the formation of the actin-rich cell protrusions, invadopodia. In this study, we show that ATX is implicated in the formation of invadopodia in various
cancer cells types and this effect is dependent on the production of LPA. We further provide evidence that LPA(4) signaling in
fibrosarcoma cells regulates invadopodia formation downstream of ATX, a process mediated through the activation of
EPAC by
cyclic AMP and subsequent Rac1 activation. Results using LPA(4)
shRNA support the requirement of the LPA(4) receptor for cell invasion and in vivo
metastasis formation. This work presents evidence that blocking the
LPA receptor, LPA(4), in
fibrosarcoma cells could provide an additional tool to improve the efficacy of treatment of
metastasis in patients. Because
LPA receptors and ATX are currently being targeted in preclinical trials, the current findings should stimulate future studies to evaluate the expression pattern and clinical outcome of LPA(4), together with other
LPA receptors, in various
cancer patients.