Regulation of Tumor Growth and Invasion in Oral Squamous Cell Carcinoma by the Tumor Microenvironment Through the Enhancement of IGFBP-3 Expression

Anticancer Res. 2024 Dec;44(12):5337-5349. doi: 10.21873/anticanres.17361.

Abstract

Background/aim: Accumulated evidence indicates that interactions among various stromal cells within the tumor microenvironment (TME) significantly influence cancer progression. Oral cancers not diagnosed at early stages are associated with low five-year survival rates, highlighting the need for substantial improvements in patient outcomes. Understanding the interactions between cancer cells and the tumor microenvironment is crucial for identifying methods and developing treatment strategies that more effectively inhibit tumor progression and metastasis.

Materials and methods: This study investigated the roles of cancer-associated fibroblasts (CAFs) and THP-1 monocytes in tumor growth and invasion, observing changes in cancer biological characteristics through interactions with stromal cells. HSC2 oral squamous cell carcinoma (OSCC) cells were co-cultured with normal fibroblasts (NF), cancer-associated fibroblasts (CAF), or THP-1 cells. Changes in cancer cell invasion were investigated using Matrigel-coated transwell assays, collagen-based dermal equivalent assays, and in vivo mouse studies.

Results: HSC2 cells co-cultured with CAFs or THP-1 exhibited increased invasion compared to those co-cultured with normal fibroblasts (NF) in the dermal equivalent. In a mouse gingival xenograft model, cancer cells co-implanted with CAFs or THP-1 showed significantly increased tumor growth compared to those co-implanted with NF. Micro-CT (μCT) analysis revealed significant alveolar bone resorption around the mandible in tumors grown with CAFs or THP-1 cells. Conditioned media (CM) from CAFs or THP-1 significantly increased HSC2 invasion and migration, an effect that was inhibited by the protein secretion inhibitor Brefeldin (BFA). Furthermore, QuantSeq 3' mRNA sequencing indicated increased expression of IGFBP3, closely associated with cancer invasion, in HSC2 cells co-cultured with CAFs or THP-1.

Conclusion: These findings suggest that cancer cells enhance their invasive characteristics through close interactions with the surrounding stromal cells.

Keywords: Cancer-associated fibroblasts; insulin-like growth factor binding protein 3; invasion; monocytes; oral squamous cell carcinoma.

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts* / metabolism
  • Cancer-Associated Fibroblasts* / pathology
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Coculture Techniques*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3* / genetics
  • Insulin-Like Growth Factor Binding Protein 3* / metabolism
  • Mice
  • Mouth Neoplasms* / genetics
  • Mouth Neoplasms* / metabolism
  • Mouth Neoplasms* / pathology
  • Neoplasm Invasiveness*
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Squamous Cell Carcinoma of Head and Neck / metabolism
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • THP-1 Cells
  • Tumor Microenvironment*

Substances

  • Insulin-Like Growth Factor Binding Protein 3
  • IGFBP3 protein, human