Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers

Jhih-Ying Chi; Yu-Wei Hsiao; Chien-Feng Li; Yu-Chih Lo; Zu-Yau Lin; Jhen-Yi Hong; Yang-Ming Liu; Xiu Han; Shao-Ming Wang; Ben-Kuen Chen; Kelvin K Tsai; Ju-Ming Wang

doi:10.18632/oncotarget.4364

Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers

Oncotarget. 2015 Sep 15;6(27):23987-4001. doi: 10.18632/oncotarget.4364.

Authors

Jhih-Ying Chi¹, Yu-Wei Hsiao², Chien-Feng Li³, Yu-Chih Lo², Zu-Yau Lin⁴, Jhen-Yi Hong², Yang-Ming Liu², Xiu Han², Shao-Ming Wang¹, Ben-Kuen Chen², Kelvin K Tsai⁵, Ju-Ming Wang^{2

6}

Affiliations

¹ Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan R.O.C.
² Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan R.O.C.
³ Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan R.O.C.
⁴ Cancer Center and Division of Hepatobiliary Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Taiwan R.O.C.
⁵ National Institute of Cancer Research and Translational Center for Glandular Malignancies, National Health Research Institutes, Tainan, Taiwan R.O.C.
⁶ Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan R.O.C.

Abstract

The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers.

Keywords: CAFs; CEBPD; PTX3; TAMs; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry*
Apoptosis / drug effects
C-Reactive Protein / antagonists & inhibitors
C-Reactive Protein / chemistry*
C-Reactive Protein / metabolism*
CCAAT-Enhancer-Binding Protein-delta / metabolism*
Cell Line, Tumor
Cell Movement
Cell Survival
Cell Transformation, Neoplastic / genetics
Cisplatin / chemistry
Culture Media, Conditioned / chemistry
Disease Progression
Drug Resistance, Neoplasm*
Female
Fibroblasts / drug effects
Fibroblasts / metabolism
Fluorouracil / chemistry
Gene Expression Regulation, Neoplastic
Humans
Macrophages / drug effects
Macrophages / metabolism
Mice
Mice, Inbred BALB C
Myofibroblasts / drug effects
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasm Transplantation
Neoplasms / metabolism
Peptide Fragments / chemistry*
Reverse Transcriptase Polymerase Chain Reaction
Serum Amyloid P-Component / antagonists & inhibitors
Serum Amyloid P-Component / chemistry*
Serum Amyloid P-Component / metabolism*
Tumor Microenvironment / drug effects

Substances

Antineoplastic Agents
Culture Media, Conditioned
Peptide Fragments
Serum Amyloid P-Component
pentraxin 3 (200-236)
CCAAT-Enhancer-Binding Protein-delta
PTX3 protein
C-Reactive Protein
Cisplatin
Fluorouracil