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Silencing of the Genes

September 23, 2015

Silencing of the Genes

Grim Statistics

It spreads quickly, usually before any noticeable symptoms. Because there is no accurate way to diagnose pancreatic cancer early, by the time it manifests itself as a full-blown tumor, its diagnosis can often be devastating. Despite aggressive radiation, chemotherapies, surgical procedures, and ongoing research, pancreatic cancer is typically resistant to current treatments. Thanks to circulating tumor cells, it also spreads rapidly. Most pancreatic cancer patients are dead in a year. Within five years, 97% of its victims die.1 The disease is so lethal, experts predict it will become the second leading cause of cancer deaths in the U.S. by 2020.2 That is, unless the recent discovery by a team of molecular scientists and medical engineers provides the proverbial key to finally suppressing this deadly killer.3

Cancer’s Pathways

Metastasis is Greek, meaning displacement. In medicine, it defines the spread of disease. An existing cancer, for instance, sometimes sheds circulating tumor cells (CTCs) into the bloodstream to spread the disease to other parts of the body. Considered rare, CTCs remained a mystery and were poorly understood... until now.

Two dozen researchers from Harvard and Massachusetts General Hospital, among other institutions, worked together to create a microfluidic technology that isolated CTCs for the first time. The CTCs in question originated from blood samples of genetically engineered mice with pancreatic cancer as well as human patients with the disease. The team submitted these samples to single-molecule RNA-based sequencing to develop a gene expression profile. Researchers then ran cell cultures and visualized immunoblots of the proteins using an ultra-sensitive PerkinElmer® Western LightingTM Plus Chemiluminescence kit. The kit produces non-radioactive light designed to detect proteins with a sensitive camera. Protein profiles were subsequently compared to a profile of a primary pancreatic tumor as well as healthy pancreatic tissue. In doing so, researchers noticed that one gene in particular, Wnt2, stuck out for its overexpression as the most likely candidate to promote the spread of pancreatic cancer.4

After tagging the Wnt2 gene with a bioluminescent enzyme called luciferase, mice were injected with the luminescent gene solution, and were then monitored daily with a PerkinElmer® IVIS® LuminaTM Pre-clinical In Vivo Imaging System at Harvard Medical School for a period of six weeks.5 As the industry standard in bioluminescence and fluorescence imaging, the Lumina II also imaged Wnt2 cells in a separate assay procedure that monitored the genes’ regulation of signaling pathways in the cells.6

From Mice to Men

Building on their Wnt2 observations, researchers turned their attention to identifying potential inhibitors of Wnt2-related pathways in humans. Testing 66 human blood samples, they found Wnt2 in 23 and CTC counts above the threshold in 11. Following the same procedures for discovering CTCs in mice, the team then analyzed the 11 human samples and found a strong Wnt2 signaling pathway component. Among four healthy control samples, no such link was found. The results suggested that Wnt2 pathways might well contribute to metastasis in human pancreatic cancer.

Possible Pathways to New Treatments

Even more significant was the team’s discovery of potential inhibitors of Wnt2’s signaling capabilities. Among these inhibitors, AZ-oxozeaenol, an antibiotic, completely annulled Wnt2-induced tumor-sphere growth.

“In humans, formation of non-adherent tumor spheres by pancreatic cancer cells is associated with upregulation of multiple WNT genes, and pancreatic CTCs revealed enrichment for WNT signaling in 5 out of 11 cases,” Yu’s team said. “Thus, molecular analysis of CTCs may identify candidate therapeutic targets to prevent the distal spread of cancer.”7

Dr. Yu now runs his own research lab at the University of Southern California. His specialty? The war on cancer and his ongoing focus on CTCs. Based on his earlier research, Yu believes that CTCs now contain cancer stem cells, and he is determined to not merely find them, but develop new therapeutic approaches for targeting the metastatic tumor initiating cells, themselves, he says.8

References

  1. Significant Breakthrough In Pancreatic Cancer Treatment,” Fred Hutchinson Cancer Research Center, Annual Report, 2012.
  2. Pancreatic Cancer Facts 2014, Pancreatic Cancer Action Network.
  3. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis, Nature, July 2012.
  4. WNT Signaling Enhances the Metastatic Potential of Pancreatic Tumors, Cancer Discovery, August 2, 2012.
  5. Harvard Medical School Core Facilities.
  6. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis, Nature, July 2012.
  7. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis, Nature, July 2012.
  8. Yu Lab, University of Southern California Stem Cell Lab Overview.

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