• January 2020

    New findings address role of sonic hedgehog signaling in pancreatic cancer pain

Findings from a recent study demonstrate a significant correlation between the sonic hedgehog (sHH) signaling pathway and pancreatic cancer (PC) pain. BSWRI researcher Erxi Wu, Ph.D. was among the researchers who led this work and helped author a paper detailing the findings, which was published in Regional Anesthesia & Pain Medicine.

The paper, “Sonic hedgehog signaling pathway promotes pancreatic cancer pain via nerve growth factor,” was written with researchers at Xi’an Jiaotong University in China.

Abdominal and back pain is a common occurrence in PC patients however, the exact cause of this pain is largely unknown beyond the understanding that pain is the outcome of some type of interaction between nerves and PC.

The sHH ligand is one of the most studied Hedgehog signaling pathways. sHH is known for its involvement in controlling the rapid replication of adult stem cells, but it has also been closely linked to certain cancers. Specifically, sHH is found at more elevated levels in human PC tissue versus normal pancreatic tissue, and recent studies have demonstrated that expression of the sHH ligand contributes to PC progression. Additionally, paracrine sHH signaling is known to play a role in communication between the tumor, stroma and nerves.

Given this, the researchers hypothesized that a potential direct influence exists between the sHH signaling pathway and pancreatic cancer pain expression.

The study was designed with specific objectives in mind. These included:

  1. Determine a primary dose-effect relationship between sHH and pain factors
  2. Determine whether PC cells mediate pancreatic pain by sHH
  3. Determine if sHH secretion from PC cells activates the sHH signaling pathway in diagnosis related groups (DRGs)
  4. Determine if the activation of the sHH signaling pathway significantly contributes to the induction of nerve growth factor and receptors in DRGs
  5. Determine whether sHH and nerve growth factor/nerve growth factor receptor mediate PC-associated pain behavior in a mouse model

Per the authors, the study produced key findings that reinforce the hypothesis that PC pain originates from the sHH signaling pathway:

  • Expression and secretion of inflammatory neuropeptides SP and CGRP were dependent on the timing and concentration of sHH activity in DRGs
  • Exploration of sHH expression in PC cells found the ligand acted in a paracrine manner on DRGs to increase sHH signaling activation – a new model of cancer-nerve interaction
  • sHH was also found to increase the expression of nerve growth factor in an sHH-dependent manner in DRGs

“Our findings strengthen the rationale for PC-associated pain generation,” said Wu. “There is a growing body of work supporting the idea that the tumor microenvironment plays a considerable role in cancer cell replication, progression, and therapy response. Further exploration of the interaction between tumor stroma and PC cells could represent another promising therapeutic option for PC patients.”

In addition to this work, Dr. Wu’ s research also focuses on using tools from human genomics and drug discovery to better understand the biology of brain tumors, pancreatic cancer, and neurodegenerative diseases, in order to identify more effective therapeutics.

Complete findings from the sHH NGF study can be found online.