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Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment

Emanuela Heller1, Michelle A Hurchla, Jingyu Xiang

  • 1Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Cancer Research
|December 22, 2011
PubMed

Insights

Inhibiting the Hedgehog (Hh) pathway reduces tumor growth by impacting the tumor microenvironment, including bone cells and stromal cells. This pathway is a potential therapeutic target for cancers and bone metastases.

Area of Science:

  • Oncology
  • Bone Biology
  • Cell Signaling

Background:

  • Hedgehog (Hh) signaling plays a role in bone development and cancer.
  • The tumor microenvironment significantly influences cancer progression.

Purpose of the Study:

  • To investigate the role of Hh pathway inhibition in tumor growth, focusing on its effects on the tumor microenvironment.
  • To explore Hh signaling as a therapeutic target for solid cancers and bone metastases.

Main Methods:

  • Pharmacologic inhibition of Smoothened (Smo), a Hh pathway effector.
  • Utilizing Patched (Ptch1(+/-)) heterozygous mice with enhanced Hh signaling.
  • Investigating the effects of LDE225, a Smo antagonist, on Hh-resistant tumor cells.
  • Knockdown of Sonic Hh (SHH) ligand in tumor cells.

Main Results:

  • Hh pathway inhibition increased trabecular bone and reduced osteoclastogenesis.
  • Enhanced Hh signaling led to increased bone resorption and promoted tumor growth in vivo.
  • Inhibition of Smo reduced tumor growth, even in Hh-resistant cells, by affecting the microenvironment.
  • Tumor-derived SHH stimulated tumor growth via paracrine signaling, decreasing stromal interleukin-6 production.

Conclusions:

  • Hh pathway inhibition effectively reduces tumor burden by targeting tumor cells, osteoclasts, and stromal cells within the tumor microenvironment.
  • The Hh pathway is a promising therapeutic target for solid cancers and bone metastases, irrespective of tumor Hh responsiveness.

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