Abstract
Tumor cell extravasation is a determinant step in the process of hematogenous metastasis. The signal transduction pathways involved in the interactions between tumor cells and the vascular endothelium during transendothelial migration are still undefined. In the present study, we have investigated the influence of human breast adenocarcinoma cells (MCF7) on human umbilical vein endothelial cell (HUVEC) intracellular Ca2+ concentration ([Ca2+]i). We show that the contact between MCF7 cells and a confluent HUVEC monolayer induces an immediate and transient increase in HUVEC [Ca2+]i. This [Ca2+]i rise could not be elicited by tumor cell-conditioned medium, isolated tumor cell membranes, inert beads or normal breast epithelial cells, demonstrating the involvement of specific recognition mechanisms between MCF7 cells and HUVEC. Depletion of HUVEC intracellular Ca2+ stores by the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin as well as the selective depletion of inositol 1,4,5-tri phosphate (IP3)-sensitive Ca2+ stores by prior activation of HUVEC using histamine resulted in a complete inhibition of tumor cell-induced [Ca2+]i elevation. Similar results were obtained when HUVEC monolayers were treated with the tyrosine kinase inhibitor herbimycin A, suggesting a role for tyrosine kinase-associated cell surface receptors in tumor cell-endothelial cell interactions. The depletion of HUVEC intracellular Ca2+ stores by thapsigargin was also shown to delay MCF7-induced endothelial cell disjunction, to prevent their spreading on the subendothelial extracellular matrix and transendothelial migration in vitro. These results suggest that transient changes in endothelial [Ca2+]i may govern multiple steps of tumor cell extravasation. © Rapid Science 1998
Similar content being viewed by others
References
Nicolson GL, 1989, Metastatic tumor cell interactions with endothelium, basement membrane and tissue. Curr Opin Cell Biol 1, 1009–19.
Honn KV and Tang DG, 1992, Adhesion molecules and tumor cell interaction with endothelium and subendothelial extracellular matrix. Cancer Metastasis Rev 11, 353–75.
Chambers AF, McDonald IC, Schmidt EE et al. 1995, Steps in tumor metastasis: new concept for intravital videomicroscopy. Cancer Metastasis Rev 14, 279–301.
Incardona F, Lewalle JM, Morandi V et al. 1995, Thrombospondin modulates human breast adenocarcinoma cell adhesion to human vascular endothelial cells. Cancer Res 55166–73.
Curry FE, 1992, Modulation of venular microvessel permeability by calcium influx into endothelial cells. FASEB J 6, 2456–66.
Retrosen D and Gallin JI, 1986, Histamine type I receptor occupancy increases endothelial cytosolic calcium, reduces F-actin, and promotes albumin diffusion across cultured endothelial monolayers. J Cell Biol 103, 2379–87.
Erhinger WD, Edwards MJ and Miller FN, 1996, Mechanisms of a-thrombin, histamine, and bradykinin induced endothelial permeability. J Cell Physiol 167, 562–69.
Huang AJ, Manning JE, Bandak TM, et al. 1993, Endothelial cell cytosolic free calcium regulates neutrophil migration across monolayers of endothelial cells. J Cell Biol 120, 1371–80.
Ziegelstein RC, Corda S, Pili R, et al. 1994, Initial contact and subsequent adhesion of human neutrophils or monocytes to human aortic endothelial cells releases an endothelial intracellular calcium store. Circul 90, 1899–907.
Pfau S, Leitenberg D, Rinder et al. 1995, Lymphocyte adhesion-dependent calcium signaling in human endothelial cells. J Cell Biol 128, 969–78.
Pili R, Corda S, Passaniti A, et al. 1993, Endothelial cell Ca2+ increases upon tumor cell contact and modulates cell-cell adhesion. J Clin Invest 92, 3017–22.
Jaffe EA, Nachman RL, Becker CG and Minick CR, 1973, Culture of human endothelial cells derived from umbilical veins. J Clin Invest 52, 2745–56.
Soule HD, Vazquez J, Long A, et al. 1973, Human cell line from pleural effusion derived from breast carcinoma. J Natl Cancer Inst 51, 1409–13.
Soule HD and McGrath C, 1986, A simple method for passage and long-term growth of human mammary epithelial cells in vitro. Cell Dev Biol 22, 6–12.
Minta A, Kao JPY and Tsien RY, 1989, Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J Biol Chem 264, 8171–78.
Kao JPY, Harootunian AT and Tsien RY, 1989, Photochemically generated cytosolic calcium pulses and their detection by Fluo-3. J Biol Chem 264, 8179–84.
Pollock WK, Wregget KA and Irvine RF, 1988, Inositol phosphate production and Ca2+ mobilization in human umbilical vein endothelial cells stimulated by thrombin and histamine. Biochem J 256, 371–76.
Brock TA and Capasso EA, 1988, Thrombin and histamine activate phospholipase C in human endothelial cells via a phorbol ester-sensitive pathway. J Cell Physiol 136, 54–62.
Berridge MJ, 1993, Inositol triphosphate and calcium signaling. Nature 361, 315–25.
Kanner SB, Grosmaire LS, Ledbetter JA and Damle NK, 1993, β2-integrin LFA-1 signaling through phospholipase C-g1 activation. Proc Natl Acad Sci USA 90, 7099–103.
Daniel JL, Dangelmaier C and Smith JB, 1994, Evidence for a role for tyrosine phosphorylation of phospholipase Cγ2 in collagen-induced platelet cytosolic calcium mobilization. Biochem J 302, 617–22.
Somogyi L, Lasic Z, Vukicevic S and Banfic H, 1994, Collagen type IV stimulates an increase in intracellular Ca2+ in pancreatic acinar cells via activation of phospholipase C. Biochem J 299, 603–11.
Price EA, Coombe DR and Murray JC, 1996, Beta-1 integrins mediate tumor cell adhesion to quiescent endothelial cells in vitro. Brit J Cancer 74, 1762–66.
Kusama T, Nakamori S, Ohigashi H, et al. 1995, Enhancement of in vitro tumor-cell transcellular migration by tumor-cell-secreted endothelial-cellretraction factor. Int J Cancer 63, 112–18.
Honn KV, Tang DG, Grossi IM, et al. 1994, Tumor cell-derived 12(S)-hydroxyeicosatetraenoic acid induces microvascular endothelial cell retraction. Cancer Res 54, 565–74.
Lafrenie R, Shaughnessy SG and Orr WF, 1992, Cancer cell interactions with injured or activated endothelium. Cancer Metastasis Rev 11, 377–88.
Abecassis J, Millon-Collard R, Klein-Soyer C et al. 1987, Adhesion of human breast cancer cell line MCF7 to human vascular endothelial cells in culture. Enhancement by activated platelets. Int J Cancer 40, 525–31.
Lum H and Malik AB, 1994, Regulation of vascular endothelial barrier function. Am J Physiol 267, L223–41.
Stasek JE and Garcia JND, 1992, The role of protein kinase C in α-thrombin-mediated endothelial cell activation. Semin Thromb Hemost 18, 117–25.
Garcia JGN, Davis HW and Patterson CE, 1995, Regulation of endothelial cell gap formation and barrier dysfunction: role of myosin light chain phosphorylation. J Cell Physiol 163, 510–22.
Putney JW and Bird GStJ, 1993, The inositol phosphate -calcium signaling system in nonexcitable cells. Endocrine Rev 14, 610–31.
Springer TA, 1994, Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301–14.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lewalle, JM., Cataldo, D., Bajou, K. et al. Endothelial cell intracellular Ca concentration is increased upon breast tumor cell contact and mediates tumor cell transendothelial migration. Clin Exp Metastasis 16, 21–29 (1998). https://doi.org/10.1023/A:1006555800862
Issue Date:
DOI: https://doi.org/10.1023/A:1006555800862