Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression

Abstract

CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1). The product of CD82 is KAI1, a 40- to 75-kDa tetraspanin cell-surface protein also known as the leukocyte cell-surface marker CD82 (refs. 1,2). Downregulation of KAI1 has been found to be clinically associated with metastatic progression in a variety of cancers, whereas overexpression of CD82 specifically suppresses tumor metastasis in various animal models. To define the mechanism of action of KAI1, we used a yeast two-hybrid screen and identified an endothelial cell-surface protein, DARC (also known as gp-Fy), as an interacting partner of KAI1. Our results indicate that the cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, and that this interaction leads to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 and p21. Furthermore, the metastasis-suppression activity of KAI1 was significantly compromised in DARC knockout mice, whereas KAI1 completely abrogated pulmonary metastasis in wild-type and heterozygous littermates. These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis.

Models, mechanisms and clinical evidence for cancer dormancy

“…This response is not mediated by its receptor, Gprotein-coupled receptor 54, suggesting that either a paracrine signalling mechanism or an alternative receptor is important. The tetraspanin protein CD82 (also known as kangai-1), which has a role in adhesion signalling, inhibits mouse melanoma cell metastases when bound to the endothelial cell-expressed ligand DARC (Duffy antigen chemokine receptor, which is also known as CD234) 36 . In vitro analysis implicated tumour cell senescence that was induced by the CD82-DARC interaction as the inhibitory mechanism 36 .…”

NM23 et les genès Suppresseurs de métastases

“…D'autres études rapportent que l'activité anti-métastatique de KAI1 pourrait être due à l'inhibition de l'activation de MET ou de la kinase Src [29]. Récemment, l'équipe de K. Watabe a montré que la fonction anti-métastatique de KAI1 dépendait d'une interaction directe entre KAI1 des cellules tumorales et le récepteur DARC présent à la surface des cellules endothéliales, induisant une inhibition de la prolifération et la sénescence des cellules tumorales, et ainsi la suppression des métastases [30]. En effet, l'injection intraveineuse de cellules de mélanome B16F10 surexprimant KAI1 à des souris invalidées pour DARC induit la formation de métastases pulmonaires alors que l'injection de ces mêmes cellules à des souris sauvages inhibe la dissé-mination métastatique, suggérant que la fonction anti-métastatique de KAI1 est dépendante de la présence de DARC.…”

KAI1/CD82 is a novel target of estrogen receptor‐mediated gene repression and downregulated in primary human breast cancer

“…[2][3][4] Ectopic expression of KAI1 suppresses the metastatic phenotype of AT6.1 and LNCaP prostate cancer cells and of B16BL6 melanoma cells in experimental animal models. [5][6][7] In line with this, human prostate cancer and melanoma cell lines of metastatic origin lack expression of KAI1. 8 Therefore, KAI1 is widely perceived as a metastasis suppressor and has been suggested to represent a promising biomarker for the metastatic potential in human malignancies.…”

“…13 However, attempts at elucidating how KAI1 inhibits tumor growth and formation of metastases have recently made significant progress. 7,9,14 Bandyopadhyay et al demonstrated that KAI1 mediates growth-suppressive signals, which lead to induction of p21 and inhibition of tumor cell proliferation in response to stimulation with an agonistic anti-KAI1 antibody or an appropriate interacting protein like DARC. 7,9 In addition, KAI1 interferes with activation of the tyrosine kinase cMet resulting in a reduction of invasiveness of human prostate cancer cell lines.…”

“…7,9,14 Bandyopadhyay et al demonstrated that KAI1 mediates growth-suppressive signals, which lead to induction of p21 and inhibition of tumor cell proliferation in response to stimulation with an agonistic anti-KAI1 antibody or an appropriate interacting protein like DARC. 7,9 In addition, KAI1 interferes with activation of the tyrosine kinase cMet resulting in a reduction of invasiveness of human prostate cancer cell lines. 14 In comparison with prostate cancer and melanoma, the role of KAI1 in breast cancer remained less well defined.…”