Nature Reviews Cancer: Looking back at 50 years of gap junctions and cancer

Dale Laird

For 50 years researchers have understood that gap junctions play a role in cancer, but how we understand that role has changed drastically over the last five decades.

In a newly published timeline article in the high impact journal, Nature Reviews Cancer, Dale Laird, PhD, and his colleagues from around the globe look back at the progression of our understanding of gap junctions and cancer and highlight important unanswered questions, controversies and therapeutic opportunities in the field.

“Reviews like this take a big picture look at a complex problem and ask, ‘can we weave together a meaningful story?’” said Laird. “This article really distills more than 1500 publications on gap junctions in cancer and allows us to look at whether we are going down the right path with thoughts toward the future.”

Laird and his co-authors are world leaders in the study of gap junctions – the signaling system between cells that allow them to communicate with each other by literally connecting the inside of one cell with the inside of the next.

The researchers begin their review looking back at research in 1966 when scientists found that tumour cells lacked electrical coupling, leading to the notion that loss of communication between cells through gap junctions was linked with cancer onset and progression. The hypothesis at the time was that the connexin proteins associated with gap junctions were common cancer suppressors, and researchers continued for the next three decades to try to understand exactly why that was the case.

The review article follows the research through to the early 1990s when scientists began looking at the role of gap junctions in delivering therapeutics.

The field eventually evolved to show that while connexins were tumour suppressors early on in the disease, they were actually up-regulated at later stages of some cancers, and could actually be advancing disease. The review also points out that this phenomenon varied depending on the type of cancer.

“The story that these are universally good tumour-suppressors is gone,” said Laird. “But it also raises the possibility that there could be utility in targeting and using these connexins in therapeutics.”

Laird and his co-authors highlight the importance of personalized medicine in the future and state that, “the analysis of how gap junctions contribute to the physiology and pathology of patient-specific tumours will be highly informative.”

The paper was truly an international effort and was co-authored by Trond Aasen at the Translational Molecular Pathology, Vall d’Hebron Institute of Research in Barcelona, Spain; Marc Mesnil from STIM Laboratory in Poitiers, France; Christian Naus with the Department of Cellular and Physiological Sciences at the University of British Columbia in Vancouver, B.C.; and Paul Lampe, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.