TNF signaling mediates an enzalutamide-induced metastatic phenotype of prostate cancer and microenvironment cell co-cultures.

Oncotarget
Kai ShaJohn J Krolewski

Abstract

The dramatic responses tumors display to targeted therapies are limited by acquired or pre-existing mechanisms of therapy resistance. We recently discovered that androgen receptor blockade by the anti-androgen enzalutamide paradoxically enhanced metastasis and that these pro-metastatic effects were mediated by the chemoattractant CCL2. CCL2 is regulated by TNF, which is negatively regulated by androgen signaling. Thus, we asked if TNF mediates the pro-metastatic effects of enzalutamide. We found that androgen withdrawal or enzalutamide induced TNF mRNA and protein secretion in castration resistant prostate cancer (C4-2) cells, but not in macrophage-like (THP1) or myofibroblast-like (WPMY1) cells. Androgen deprivation therapy (ADT) induced autocrine CCL2 expression in C4-2 (as well as a murine CRPC cell line), while exogenous TNF induced CCL2 in THP1 and WPMY1. TNF was most potent in myofibroblast cultures, suggesting ADT induces CCL2 via paracrine interactions within the tumor microenvironment. A soluble TNF receptor (etanercept) blocked enzalutamide-induced CCL2 protein secretion and mRNA, implying dependence on secreted TNF. A small molecule inhibitor of CCR2 (the CCL2 receptor) significantly reduced TNF induced migration, wh...Continue Reading

References

Aug 1, 1980·International Journal of Cancer. Journal International Du Cancer·S TsuchiyaK Tada
May 1, 1994·International Journal of Cancer. Journal International Du Cancer·H C WuL W Chung
Jul 6, 2002·Science·I Bernard Weinstein
Jun 18, 2003·Journal of Cellular Physiology·Kent L NastiukJohn J Krolewski
Jul 16, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Yan Ping YuJian-Hua Luo
Nov 19, 2004·Nature·Charles Sawyers
Dec 30, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vincent FradetFred Saad
Feb 25, 2005·The New England Journal of Medicine·Susumu KobayashiBalázs Halmos
May 18, 2005·Proceedings of the National Academy of Sciences of the United States of America·Eunice L KwakDaniel A Haber
Mar 1, 2006·Molecular Cancer Therapeutics·Peter W SzlosarekFrances R Balkwill
Mar 16, 2007·Neoplasia : an International Journal for Oncology Research·Daniel R RhodesArul M Chinnaiyan
Aug 23, 2008·Cancer Biology & Therapy·Kent L Nastiuk, John J Krolewski
Feb 4, 2009·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Zehra KaymakcalanEric H Sasso
May 16, 2009·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Satish L DeshmaneBassel E Sawaya
Dec 17, 2009·Cytokine & Growth Factor Reviews·Jian ZhangKenneth J Pienta
Feb 5, 2011·Molecular Endocrinology·Jennifer S DavisJohn J Krolewski
Jun 22, 2011·Cell and Tissue Research·Michael K WendtWilliam P Schiemann
Jun 23, 2012·Nature·Catherine S GrassoScott A Tomlins
Aug 17, 2012·Future Oncology·Mark R LacknerJeff Settleman
Oct 18, 2013·Nature Reviews. Cancer·Michael PickupHarold L Moses
May 9, 2014·Science·Ruth A FranklinMing O Li
Sep 4, 2014·The New England Journal of Medicine·Emmanuel S AntonarakisJun Luo

❮ Previous
Next ❯

Citations

Nov 6, 2017·Pathology Oncology Research : POR·Laszló ZoltanSzabolcs Bellyei
Jan 5, 2021·Journal of Experimental & Clinical Cancer Research : CR·Hao TianChawnshang Chang
Feb 6, 2021·Cancers·María Florencia MercoglianoRoxana Schillaci
Apr 15, 2017·Seminars in Cancer Biology·Kiera RycajDean G Tang

❮ Previous
Next ❯

Methods Mentioned

BETA
xenograft
ELISA
in
xenografts
FCS

Software Mentioned

Oncomine
JMP
- Pro10

Related Concepts

Related Feeds

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.