Research in our laboratory investigates cellular and molecular mechanisms at the fetal-maternal interface responsible for human placental development in health and disease, and those responsible for invasion and metastasis in breast cancer with a goal to prevent certain fetal-maternal maladies, and to develop new modes of breast cancer therapy.
The human placenta, an essential organ for fetal survival, is a highly invasive pseudo-tumor-like structure in which certain placental cells known as the extravillous trophoblast (EVT) invade the uterus and its arteries to derive adequate nutrients for the fetus. Poor EVT cell invasion of uterine arteries results in inadequate flow of maternal blood to the placenta, which in turn, can cause poor fetal growth and also a serious pregnancy-associated disorder in the mother called preeclampsia. On the other hand, uncontrolled EVT cell invasion is a feature of trophoblastic tumors. Thus EVT cell invasiveness must be exquisitely regulated in situ to maintain a healthy utero-placental homeostasis. Our research has identified many molecules produced at the fetal-maternal interface which regulate EVT cell growth, migration and invasiveness in a positive or a negative manner, as well as the signaling mechanisms responsible for such regulation. Certain molecular/genetic alterations causing trophoblast hyper-invasiveness (in trophoblastic pre-cancer or cancer) or hypo-invasiveness (e.g. in preeclampsia) have also been identified. Current research focuses on the molecular mechanisms underlying the actions of prostaglandin E(PGE)2, an invasion-promoting molecule, and decorin, an invasion-inhibitory molecule, both produced by decidual cells of the pregnant uterus, where EVT cells invade.
Our past research on the mechanisms of cancer growth and spread had led to new protocols for treating certain human cancers with success. Present research focuses on human breast cancer. It revolves around our discoveries that aberrant expression of Cyclooxygenase (COX)-2 (an enzyme responsible for high PGE2 production) by cancer cells, promotes breast cancer progression and metastasis by multiple cellular events: (a) an inactivation of cancer-fighting immune cells, (b) a stimulation of cancer cell migration and invasiveness, (c) a stimulation of tumor-associated angiogenesis (formation of new blood vessels to feed the tumor), and (d) a stimulation lymphangiogenesis (formation of new lymphatics, that support lymphatic metastasis). Molecular mechanisms and signaling pathways underlying all these events are under study to identify appropriate molecular targets for breast cancer therapy.
• Iacob D., Cai J., Tsonis M., Babwah A., Chakraborty C., Bhattacharjee R.N. and Lala, P.K. (2008) Decorin-mediated inhibition of proliferation and migration of the human trophoblast via different tyrosine kinase receptors. Endocrinology, 149(12), 6187-97, epub, 14 August 2008
• Ajayai, F., Congosa, N., Gaffey, T., Asman, Y.W., Watson, W., Baldi, A., Lala, P.K., Shridhar, V., Brost, B. and Chien, J. (2008) Elevated expression of serine protease HtrA1 inn preeclampsia and its role in trophoblast migration and invasion Amer J Obstet. Gynecol.199, issue 5, November, 557. e1-557.e10.
• Nicola, C., Lala, P.K. and Chakraborty, C. (2008) Prostaglandin(PG)E2-mediated migration of human trophoblast requires Rac1 and Cdc42 GTPases. Biol. Reprod 78, 976-982
• Nicola, C., Chirpac,A., Lala, P.K. and Chakraborty,C (2007) Roles of Rho guanosine triphosphatase A, Rho kinases and extracellular signal regulated kinases (1/2) in Prostaglandin E2-mediated migration of first trimester human extravillous trophoblast. Endocrinology., 149(3) 1243-51, Epub 13 December, 2007
Timoshenko, A.V., Rastogi,S. and Lala, P.K. (2007) Migration-promoting role of VEGF-C and VEGF-C binding receptor in human breast cancer cells. Brit. J. Cancer 97 (10), 1090-1098,
• Timoshenko, A.V., Chakraborty, C., Wagner, G.F., and Lala, P.K. (2006) COX-2-mediated upregulation of the lymphangiogenic factor VEGF-C in human breast cancer. British. J. Cancer 94(8), 1154-63, 2006
• Zygmunt, M., McKinnon, T., Heer, F., Lala, P.K. and Han, V.K.M. (2005) HCG increases trophoblast migration in vitro via the insulin-like growth factor-II/mannose-6 phosphate receptor. Mol Hum Reprod. Apr; 11(4): 261-7.
• Nicola, C., Timoshenko, A.V., Dixon, J., Lala P.K. and Chakraborty, C. (2005) EP1 receptor-mediated migration of the first trimester human extravillous trophoblast: the role of intracellular calcium and calpain. J Clin Endocrinol Metab. 90(8): 4736-46.
• Munir, S., Xu, G., Wu, Y., Yang, B., Lala, P.K. and Peng, C. (2004) Nodal and activin receptor-like kinase (ALK) 7 inhibits proliferation and induce apoptosis in human trophoblast cells. J Biol Chem. 279; (30): 31277-31286.
• Timoshenko, A. V., Lala, P. K., Chakraborty, C. (2004) PGE2-mediated up-regulation of iNOS in murine breast cancer cells through the activation of EP4 receptors. Int. J. Cancer , 108: 384-389.
• Timoshenko, A.V., Xu, G., Chakrabarti, S., Lala, P.K., and Chakraborty, C. (2003) Role of postaglandin E2 receptors in migration of murine and human breast cancer cells. Exp Cell Res. 289(2): 265-74.
• Jadeski, L.C., Chakraborty, C., and Lala, P. K.(2003) Nitric Oxide-mediated promotion of mammary tumor cell migration requires sequential activation of Nitric Oxide synthase, guanylate cyclase and MAP Kinase. Int. J. Cancer. 106: 496-504.
• Lala, P.K. and Chakraborty, C. (2003) Factors regulating trophoblast migration and invasiveness: Possible derangements contributing to preeclampsia and fetal injury (current topic). Placenta , 24; (6): 575-587.
• Chakraborty, C., Barbin, Y.P., Dixon, S.J., Chakraborty, S., Chidiac, P. and Lala, P.K. (2003) Endothelin-1 promotes migration, elevation of [Ca++]i and phosphorylation of MAP kinase in a human extravillous trophoblast cell line. Mol. Cell Endcrinol. 201: 63-73.