Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C

Ovarian cancer is characterized by metastases to the peritoneal surface lining the abdominal cavity. It remains unclear which factors promote the implantation of ovarian cancer cells onto the peritoneal lining. We have recently investigated interactions between ovarian cancer cells (OVCAR-5, OVCAR-3, and SKOV-3) and mesothelial cells isolated from omental tissues (LP-9). We conducted a proteomic screen of the conditioned medium of co-cultures of ovarian cancer and mesothelial cells. One of the molecules identified to be modulated is the extracellular matrix adhesion protein, transforming growth factor-beta-induced protein (TGFβI, also known as b ig-H3 or keratoepithelin) which is induced by transforming growth factor-beta in many cell types which has been shown to promote adhesion and migration of hepatoma and astrocytoma cells and enhance colon cancer cell extravasation. In this study we investigated the expression of TGFβI in ovarian cancer tissues and the effects of recombinant TGFβI on ovarian cancer motility and adhesion to peritoneal mesothelial cells. In functional assays, treatment with recombinant TGFβI significantly increased adhesion of all three ovarian cancer cell lines to LP-9 mesothelial cells by up to 25% (P<0.01) and increased motility in OVCAR-5 cells by 62% (P<0.001). Furthermore, addition of a neutralising TGFβI antibody reduced OVCAR-5 adhesion to LP-9 to 79% of control level (P<0.001). TGFβI produced by LP-9 cells was processed to smaller forms when co-cultured with ovarian cancer cell lines by western blotting. MALDI-TOF/TOF mass spectrometry identified TGFβI processing at both the N and C terminal domains. The addition of broad spectrum protease inhibitors blocked the TGFβI processing and reduced OVCAR-5 adhesion to LP-9 cells to 60% of control level (P<0.001). We conclude that although some ovarian cancer cells produce low levels of TGFβI, TGFβI abundantly expressed by peritoneal mesothelial cells can promote ovarian cancer cell adhesion and motility.

Download Full-text

Faculty Opinions recommendation of Protein kinase A activity and anchoring are required for ovarian cancer cell migration and invasion.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13361012.14731132 ◽

2011 ◽

Author(s):

Alexey Tepikin

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Protein Kinase ◽

Protein Kinase A ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Migration And Invasion ◽

Cancer Cell Migration ◽

Cell Migration And Invasion ◽

Kinase A

Download Full-text

Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

Endocrine Related Cancer ◽

10.1677/erc-09-0152 ◽

2010 ◽

Vol 17 (2) ◽

pp. 335-349 ◽

Cited By ~ 29

Author(s):

Inga Mertens-Walker ◽

Christine Bolitho ◽

Robert C Baxter ◽

Deborah J Marsh

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Protein Kinase ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Cancer Cell Migration ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Gf 109203X ◽

Cell Migration And Proliferation

The gonadotropin hypothesis proposes that elevated serum gonadotropin levels may increase the risk of epithelial ovarian cancer (EOC). We have studied the effect of treating EOC cell lines (OV207 and OVCAR-3) with FSH or LH. Both gonadotropins activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and increased cell migration that was inhibited by the MAPK 1 inhibitor PD98059. Both extra- and intracellular calcium ion signalling were implicated in gonadotropin-induced ERK1/2 activation as treatment with either the calcium chelator EGTA or an inhibitor of intracellular calcium release, dantrolene, inhibited gonadotropin-induced ERK1/2 activation. Verapamil was also inhibitory, indicating that gonadotropins activate calcium influx via L-type voltage-dependent calcium channels. The cAMP/protein kinase A (PKA) pathway was not involved in the mediation of gonadotropin action in these cells as gonadotropins did not increase intracellular cAMP formation and inhibition of PKA did not affect gonadotropin-induced phosphorylation of ERK1/2. Activation of ERK1/2 was inhibited by the protein kinase C (PKC) inhibitor GF 109203X as well as by the PKCδ inhibitor rottlerin, and downregulation of PKCδ was inhibited by small interfering RNA (siRNA), highlighting the importance of PKCδ in the gonadotropin signalling cascade. Furthermore, in addition to inhibition by PD98059, gonadotropin-induced ovarian cancer cell migration was also inhibited by verapamil, GF 109203X and rottlerin. Similarly, gonadotropin-induced proliferation was inhibited by PD98059, verapamil, GF 109203X and PKCδ siRNA. Taken together, these results demonstrate that gonadotropins induce both ovarian cancer cell migration and proliferation by activation of ERK1/2 signalling in a calcium- and PKCδ-dependent manner.

Download Full-text