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Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies

L A Hazlehurst1, W S Dalton

  • 1Department of Interdisciplinary Oncology, University of South Florida, Tampa, USA.

Cancer Metastasis Reviews
|February 8, 2002
PubMed

Insights

Tumor microenvironment interactions, like cell adhesion to fibronectin, can cause drug resistance in hematopoietic tumors by inhibiting apoptosis and blocking cell cycle progression. Understanding these mechanisms may reveal new targets to overcome resistance.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • The tumor microenvironment, comprising soluble factors, extracellular matrix, and cell interactions, significantly influences tumor response to chemotherapy.
  • Cell-cell and cell-matrix interactions lead to cytoskeletal changes and signaling pathway activation, impacting cell survival, growth, and differentiation.
  • Anti-apoptotic pathways activated by cell adhesion contribute to drug resistance in tumor cells against various chemotherapeutic agents.

Purpose of the Study:

  • To investigate the role of cell adhesion within the tumor microenvironment in mediating resistance to chemotherapeutic agents.
  • To explore the mechanisms by which cell adhesion to fibronectin affects hematopoietic tumor cells and their response to cytotoxic drugs.

Main Methods:

  • Experimental investigation of hematopoietic tumor cell lines.
  • Analysis of cell adhesion to fibronectin.
  • Assessment of apoptosis, cell cycle progression, p27kip1 levels, and DNA damage induced by chemotherapeutic agents.

Main Results:

  • Cell adhesion to fibronectin is sufficient to inhibit apoptosis induced by distinct cytotoxics in hematopoietic tumors.
  • Adhesion to fibronectin blocks cell cycle progression, evidenced by increased p27kip1 levels and cell cycle arrest in multiple myeloma cells.
  • Adherent hematopoietic tumor cells exhibit reduced initial DNA damage from topoisomerase II inhibitors.

Conclusions:

  • Cell adhesion-mediated drug resistance (CAM-DR) is a significant factor in tumor response to chemotherapy.
  • Fibronectin-mediated adhesion confers resistance in hematopoietic tumors through mechanisms involving cell cycle arrest and reduced DNA damage.
  • Further research into CAM-DR mechanisms could identify novel therapeutic targets for reversing de novo drug resistance.

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