Exosomes Mediate Stromal Mobilizaion of Autocrine Wnt-PCP Signaling in Breast Cancer Cell Migration. (Cell 2012, 151:1542-1556)

報告日期: 2013/05/03
報告時間: 15:10/16:00
報告學生: 董家豪
講評老師: 呂佩融
附件下載: 下載[1310-1365562734-1.pdf] 

Exosomes Mediate Stromal Mobilization of Autocrine Wnt-PCP Signaling in

Breast Cancer Cell Migration

Cell. 151(7):1542-1556 (2012)

Valbona Luga, Liang Zhang, Alicia M. Viloria-Petit, Abiodun A. Ogunjimi, Mohammad R. Inanlou, Elaine Chiu,

Marguerite Buchanan, Abdel Nasser Hosein, Mark Basik, and Jeffrey L. Wrana

Speaker: Chia-Hao Tung                                         Time: 2013/5/3 15:10-16:00

Commentator: Pei-Jung Lu, PhD                                  Place: Room 602

Purpose: Direct signaling between the tumor stroma and cancer cells in metastasis remains less well-defined. Noncanonical Wnt/planar cell polarity (PCP) pathways are essential for tissue polarity and cell movement during vertebrate development and regulated by Wnt5a and Wnt111. Unlike the canonical Wnt/β-catenin signaling, the role of Wnt/PCP pathway is poorly characterized in cancer. However, in several cancers, the core PCP pathway components are overexpressed and correlated with cancer cell migration and metastasis2. The authors hypothesize that cancer associated fibroblasts (CAFs), which are abundant in tumor stroma, provide the signals to activate the Wnt/PCP pathway and promote cancer cell migration and metastasis.

Experimental Design and Results: The authors collect the condition media from transformed mouse fibroblast L cells, which named active-conditioned medium (ACM). After ACM treatment, the human breast adenocarcinoma MDA-MB-231 cells increase the long and dynamic protrusive structures, cell mobility and metastatic ability. RNAi suppression of the core PCP pathway components and the ligand Wnt11 inhibits ACM-induced phenotype. Analysis of the ACM components indicated that L-cell secreted exosomes and tetraspanin CD81 are important for ACM-stimulated phenotype. This phenotype is also proved in primary human breast CAFs. Based on analysis of clinical human breast cancers, CD81 is significantly upregulated in the stroma isolated from invasive ductal carcinoma compared with normal breast tissue. Furthermore, the fluorescently labeled CD81-positive exosomes are internalized by endocytosis and associated with the Wnt11 in cancer cells. Eventually, the Wnt11 ligands are taken out of the cancer cells by exosomes and redistributed to the plasma membrane. The authors think this is required for activating Wnt/PCP signaling. Collectively, fibroblast-secreted CD81-positive exosomes associate with the Wnt11 and mobilize the autocrine Wnt-PCP signaling to promote breast cancer cell protrusive activity, motility, and metastasis.

References:

1.     Gray RS et al (2011) Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity. Dev Cell. 21(1):120-33.

2.     Jessen JR. (2009) Noncanonical Wnt signaling in tumor progression and metastasis. Zebrafish. 6 (1): 21–28.