Full Text | PDF

Theranostics 2021; 11(11):5143-5159. doi:10.7150/thno.58779 This issue Cite

Research Paper

Preventing tumor progression to the bone by induced tumor-suppressing MSCs

Xun Sun^1,2, Kexin Li^1,2, Rongrong Zha^1,2, Shengzhi Liu², Yao Fan^1,2, Di Wu^1,2, Misato Hase^2,3, Uma K. Aryal⁴, Chien-Chi Lin^2,5, Bai-Yan Li^1✉, Hiroki Yokota^1,2,5,6✉

1. Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
2. Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
3. Graduate School of Engineering, Mie University, Mie 514, Japan.
4. Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA.
5. Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
6. Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

✉ Corresponding authors: Hiroki Yokota, PhD, Department of Biomedical Engineering, Indiana U. Purdue U. Indianapolis, 723 West Michigan Street, SL220, Indianapolis, IN 46202 USA. Phone: 317-278-5177, Fax: 317-278-2455, E-mail: hyokotaedu; Bai-Yan Li, MD/PhD, Department of Pharmacology, School of Pharmacy, Harbin Medical University, #157 Baojian Road, Harbin 150081, China. Phone/Fax: +86 451-8667-134, E-mail: libyhrbmu.edu.cn. More

Abstract

Background: Advanced breast cancer metastasizes to many organs including bone, but few effective treatments are available. Here we report that induced tumor-suppressing (iTS) MSCs protected bone from metastases while un-induced MSCs did not.

Methods: iTS MSCs were generated by overexpressing Lrp5, β-catenin, Snail, or Akt. Their tumor-suppressing capability was tested using a mouse model of mammary tumors and bone metastasis, human breast cancer tissues and cancer cell lines.

Results: In a mouse model, the induced MSC-derived conditioned medium (MSC CM) reduced mammary tumors and suppressed tumor-induced osteolysis. Tumor-promoting genes such as CXCL2 and LIF, as well as PDL1, a blocker of T-cell-based immune responses were downregulated. Proteomics analysis revealed that heat shock protein 90 (Hsp90ab1), calreticulin (Calr) and peptidylprolyl isomerase B (Ppib), which are highly expressed intracellular proteins in many cancers, were enriched in MSC CM as atypical tumor suppressors. Thus, overexpressing selected genes that were otherwise tumorigenic rendered MSCs the tumor-suppressing capability through the atypical suppressors, as well as p53 and Trail. Notably, the inhibitory effect of Lrp5- and Akt-overexpressing MSC CMs, Hsp90ab1 and Calr presented selective inhibition to tumor cells than non-tumor cells. The development of bone-resorbing osteoclasts was also suppressed by MSC CMs.

Conclusion: Collectively, the results showed an anti-tumor effect of iTS MSCs and suggested novel therapeutic approaches to suppress the progression of tumors into the bone.

Keywords: breast cancer bone metastasis, MSCs, Lrp5, Snail, Akt

Citation styles

©2024 Ivyspring International Publisher. Terms of use