Secreted factors from M1 macrophages drive prostate cancer stem cell plasticity by upregulating NANOG, SOX2, and CD44 through NFκB-signaling

Oncoimmunology. 2024 Aug 21;13(1):2393442. doi: 10.1080/2162402X.2024.2393442. eCollection 2024.

Abstract

The inflammatory tumor microenvironment (TME) is a key driver for tumor-promoting processes. Tumor-associated macrophages are one of the main immune cell types in the TME and their increased density is related to poor prognosis in prostate cancer. Here, we investigated the influence of pro-inflammatory (M1) and immunosuppressive (M2) macrophages on prostate cancer lineage plasticity. Our findings reveal that M1 macrophage secreted factors upregulate genes related to stemness while downregulating genes associated with androgen response in prostate cancer cells. The expression of cancer stem cell (CSC) plasticity markers NANOG, KLF4, SOX2, OCT4, and CD44 was stimulated by the secreted factors from M1 macrophages. Moreover, AR and its target gene PSA were observed to be suppressed in LNCaP cells treated with secreted factors from M1 macrophages. Inhibition of NFκB signaling using the IKK16 inhibitor resulted in downregulation of NANOG, SOX2, and CD44 and CSC plasticity. Our study highlights that the secreted factors from M1 macrophages drive prostate cancer cell plasticity by upregulating the expression of CSC plasticity markers through NFκB signaling pathway.

Keywords: Cancer cell plasticity; prostate cancer; tumor-associated macrophages.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Plasticity / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hyaluronan Receptors* / genetics
  • Hyaluronan Receptors* / metabolism
  • Kruppel-Like Factor 4* / metabolism
  • Macrophages* / metabolism
  • Male
  • Mice
  • NF-kappa B* / metabolism
  • Nanog Homeobox Protein* / genetics
  • Nanog Homeobox Protein* / metabolism
  • Neoplastic Stem Cells* / metabolism
  • Neoplastic Stem Cells* / pathology
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / metabolism
  • Prostatic Neoplasms* / pathology
  • SOXB1 Transcription Factors* / genetics
  • SOXB1 Transcription Factors* / metabolism
  • Signal Transduction*
  • Tumor Microenvironment / immunology
  • Tumor-Associated Macrophages / immunology
  • Tumor-Associated Macrophages / metabolism
  • Up-Regulation

Substances

  • Nanog Homeobox Protein
  • SOXB1 Transcription Factors
  • Hyaluronan Receptors
  • NANOG protein, human
  • SOX2 protein, human
  • Kruppel-Like Factor 4
  • NF-kappa B
  • CD44 protein, human
  • KLF4 protein, human

Grants and funding

The work was supported by the Research Council of Finland [324238, 324009, 328928, 352964, 356947, 331847, 340927], Cancer Foundation Finland, Sigrid Jusélius foundation, Finnish Cultural foundation, Finnish Cultural foundation North Savo Regional Fund, the Cancer Society of North Savo, Kuopio University foundation and Paavo Koistinen foundation.