Platelets, autotaxin and lysophosphatidic acid signalling: win‐win factors for cancer metastasis

Abstract

Platelets play a crucial role in the survival of metastatic cells in the blood circulation. The interaction of tumour cells with platelets leads to the production of plethoric factors among which our review will focus on lysophosphatidic acid (LPA), because platelets are the highest producers of this bioactive lysophospholipid in the organism. LPA promotes platelet aggregation, and blocking platelet function decreases LPA signalling and leads to inhibition of breast cancer cell metastasis. Autotaxin (ATX), a lysophospholipase D responsible for the basal concentration of LPA in blood, was detected in platelet α-granules. Functionally, active ATX is eventually released following tumour cell-induced platelet aggregation, thereby promoting metastasis. Megakaryocytes do not express ATX but respond to LPA stimulation. Whether LPA-primed megakaryocytes contribute to the recently reported negative action of megakaryocytes on cancer metastasis is not yet known. However, an understanding of the ATX/LPA signalling pathways in platelets, cancer cells and megakaryocytes opens up new approaches for fighting cancer metastasis.

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…In human breast cancer, serum ATX has since been investigated a novel biomarker for nodal disease [83]. More recent studies demonstrate that ATX produced by platelets provides LPA for establishing a hospitable niche for metastatic cancer cell seeding, further enhanced by additional signaling mediated by ATX binding to cell surface integrins at the sites of metastases [84,85]. Results from cBioPortal (www.cbioportal.org) [86,87].…”

Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

“…These experiments on ATX mRNA expression provide information on where ATX is produced before it is secreted into the tumor microenvironment where it attaches to adjacent cells including cancer cells by binding to integrins and syndecan-4. This binding appears to selectively channel LPA signaling to LPA receptors [ 68 , 69 , 70 , 71 ]. It is, therefore, concluded that most of the ATX that mediates LPA signaling is produced by adipocytes, fibroblasts, and tumor-associated stromal cells rather than the breast cancer cells themselves.…”

“…Secreted ATX binds to integrins and syndecan-4 on the surface of neighboring cells, including cancer cells. This binding appears to selectively channel LPA signaling to LPA receptors [ 68 , 69 , 70 , 71 ], which could be an important part of cancer progression.…”

Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment

“…ATX is detected in platelet α-granules. Functionally active ATX is eventually released following tumor cell-induced platelet aggregation, thereby promoting metastasis [ 66 ].…”