KISS1 tumor suppressor restricts angiogenesis of breast cancer brain metastases and sensitizes them to oncolytic virotherapy in vitro

Cancer Lett. 2018 Mar 28;417:75-88. doi: 10.1016/j.canlet.2017.12.024. Epub 2017 Dec 18.

Abstract

KISS1 tumor suppressor protein regulates cancer cell invasion via MMP9 metalloproteinase. Downregulation of KISS1 gene expression promotes progression of breast cancer and melanoma, resulting in the development of distant metastases. In the current study, we investigated whether restoration of KISS1 expression in KISS1-deficient human metastatic breast cancer cells holds potential as an advanced anticancer strategy. To this end we engineered an infectivity-enhanced conditionally-replicative human adenovirus type 5 encoding KISS1 as an "arming" transgene in the Ad5 E3 region for an ectopic KISS1 expression in transduced cancer cells. The oncolytic potential of the vector was examined using brain-invading metastatic clones of CN34 and MDA-MB-231 breast cancer cells, which supported high levels of AdKISS1 replication, correlating with a robust CRAd-mediated cytotoxicity. Secretion of cellular factors responsible for tumor angiogenesis, cell-to-cell communication and anti-tumoral immune responses upon KISS1 expression in breast cancer cells was analyzed by a RayBiotech Kiloplex Quantibody array. Overall, our results indicate that KISS1 transgene expression provides an important benefit for CRAd-mediated cytotoxicity in breast cancer cells and holds potential as an anticancer treatment in conjunction with oncolytic virotherapy of breast and other metastatic cancers.

Keywords: Adenovirus; Breast cancer metastases; Gene therapy; KISS1 tumor suppressor.

MeSH terms

  • A549 Cells
  • Adenoviridae / genetics
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / secondary
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Cells, Cultured
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor
  • Genetic Vectors / genetics
  • Humans
  • Kisspeptins / genetics*
  • Kisspeptins / metabolism
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Oncolytic Virotherapy / methods

Substances

  • KISS1 protein, human
  • Kisspeptins