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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 27 Pg. 23987-4001 (Sep 15 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26124179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Antineoplastic Agents (chemistry)
• Apoptosis (drug effects)
• C-Reactive Protein (antagonists & inhibitors, chemistry, 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, metabolism)
• Fluorouracil (chemistry)
• Gene Expression Regulation, Neoplastic
• Humans
• Macrophages (drug effects, 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, chemistry, metabolism)
• Tumor Microenvironment (drug effects)