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Breaking Down Barriers to Chemoresistance: Role of Chemotherapy-Induced Osteoblastic Jagged1

Khalid S Mohammad1, Theresa A Guise1

  • 1Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.

Cancer Cell
|December 13, 2017
PubMed

Insights

Chemotherapy can unexpectedly worsen bone metastases by making them resistant to treatment. This occurs through a mechanism involving osteoblast Jagged1 and tumor Notch signaling, highlighting a new challenge in cancer treatment.

Area of Science:

  • Oncology
  • Cancer Biology
  • Bone Metastasis Research

Background:

  • Bone metastases represent a significant clinical challenge with limited treatment options.
  • The bone microenvironment's role in cancer progression and treatment resistance has been implicated but not fully elucidated.
  • Understanding the mechanisms underlying bone metastasis chemoresistance is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the mechanisms by which chemotherapy affects the survival and resistance of bone metastases.
  • To identify specific molecular pathways in the bone microenvironment that contribute to treatment resistance.
  • To explore the role of osteoblast-tumor cell interactions in mediating chemoresistance.

Main Methods:

  • Utilized a combination of in vivo and in vitro models to study bone metastasis.
  • Analyzed gene and protein expression related to Notch signaling in osteoblasts and tumor cells.
  • Investigated the functional impact of Jagged1 and Notch pathway modulation on chemoresistance.

Main Results:

  • Chemotherapy administration was found to induce chemoresistance in established bone metastases.
  • Osteoblasts were identified as key players in mediating this resistance.
  • Specifically, osteoblast-derived Jagged1 was shown to activate tumor Notch signaling, conferring resistance to chemotherapy.

Conclusions:

  • Chemotherapy itself can paradoxically induce a chemoresistant phenotype in bone metastases.
  • The osteoblast-Jagged1-tumor Notch signaling axis is a critical mediator of this chemotherapy-induced resistance.
  • Targeting this pathway may offer novel therapeutic strategies to overcome chemoresistance in bone metastases.

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