The discovery is a major breakthrough because, until now, genetic aberrations have been seen as the main cause of almost all cancer.
The findings also open the possibility of new therapies aimed at measuring and preventing dangerous imbalances in cells.
Under normal conditions, the cell receives external signals through a cell wall-bound receptor (FGFR2 in this study). As a result of this stimulus the receptor is ‘switched on’ inside the cell. This results in the recruitment of signalling proteins and the initiation of the Akt pathway, which is responsible for committing the cell to proliferate. In some cancerous cells, this pathway is permanently switched on. A conventional approach to diagnosing this cancer would be to look for genetic modification of the receptor (or recruited proteins), which could be responsible for maintaining the switched on state.
The new study looked at isolated cancer cells without external stimulation and found that the “Akt pathway” could be activated without genetic modifications. Two proteins; Plcγ1 (pronounced “plc-gamma-1”) and Grb2 (pronounced “grab-2”), compete for binding to FGFR2. The relative concentration of these proteins will dictate which one binds. When Plcγ1 prevails, it triggers the Akt pathway. In this way, an imbalance in the amount of the two proteins can lead to cell proliferation and cancer formation.
The researchers also looked at the process in a mouse model and found that Grb2 depletion results in the development of multiple tumours in the vicinity of a primary tumour, indicating that protein imbalance can have a role in metastasis, the spread of a cancer through the body. This makes sense because Plcγ1 can play a role in increasing cell movement.
Finally, the researchers looked at whether imbalance between Grb2 and Plcγ1 was predictive of the progress of ovarian cancers in patients. Measuring the levels of the proteins in patient tissues followed by database analysis of clinical information from The Cancer Genome Atlas and other sources revealed that a high level of Grb2 relative to Plcγ1 and FGFR2 was associated with a significantly more favourable prognosis than patients with elevated levels of Plcγ1.
Statistical data reveal that just under 40% of patients with a favourable balance were still alive seven years after samples were taken. Less than 10% of patients with high levels of Plcγ1 and FGFR2 binding sites survived the same length of time.
Professor Ladbury said: “From the patient’s point of view, the key findings are that these proteins are biomarkers. They could offer information to clinicians on who is going to benefit from therapy and, just as importantly, who is not. On the treatment side, the proteins’ interaction could be a valid therapeutic target: you could, for instance, target Plcγ1 to ensure it does not overwhelm the cell.”
Previous research findings have emphasised the roots of cancer in genetic mutation. Some studies have pointed to cancers that occur without genetic causes, such as through epigenetic modifications of proteins, however the present study reveals that signalling though cell wall-based receptors can occur without receptor activation and therefore that non-genetic causes may be critical to understanding cancer in large numbers of patients.
The researchers are now working with clinicians at the University of Leeds to study the same mechanisms in other forms of cancer. They are also exploring the possibility that other cell receptors could play a similar role to FGFR2 in sustaining oncogenic signalling without being activated themselves.
The research was funded by the G. Harold and Leila Y. Mathers Charitable Foundation, the National Institute of Health (NIH), the RGK Foundation and the Gilder Foundation. It involved researchers from the University of Leeds, The University of Texas MD Anderson Cancer Center and the UT Health Science Center at Houston.
Contact: Chris Bunting, Senior Press Officer, University of Leeds; phone +44 (0)113 343 2049 or email firstname.lastname@example.org.
The full paper: Z. Timsah et al., ‘Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer’ is published in Oncogene (2015), 1-11 (DOI:10.1038/onc.2015.279; URL: http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2015279a.html)
Ralf Richter, David Brockwell, Eric Hewitt, Jessica Kwok, Emanuele Paci and MAPS/FMH, BBSRC (Jun 2017), £600,000
Eric Blair, Adrian Whitehouse, Nicola Stonehouse, Alison Baker, Richard Bayliss, Joan Boyes, Ryan Seipke, Sally Boxall and MAPS/FMH, BBSRC (Jun 2017), £376,000
Stefan Kepinski, Yoselin Benitez-Alfonso, Tom Bennett, Michelle Peckham, BBSRC (Jun 2017), £331,000
Roman Tuma, Lars Jeuken, Paul Millner, Sheena Radford, Peter Stockley and MAPS/FMH, BBSRC (Jun 2017), £222,000
Vas Ponnambalam, Darren Tomlinson, Stephen Wheatcroft, BHF (May 2017), £107,878
Graham Askew in collaboration with Bangor University, BBSRC (Mar 2017), £477,383
Stephen Muench, BBSRC (Mar 2017), £132,945
Nic Stonehouse, MRC (Mar 2017), £906,341
Bill Kunin, Steve Sait, BBSRC (Mar 2017), £602,831
Adrian Goldman, EU (Mar 2017), £546,576
Sheena Radford, Wellcome Trust (Mar 2017), £1,836,482
Tom Bennett, Royal Society (Mar 2017), £15,000
Jamie Johnston, Royal Society (Mar 2017), £15,000
Beatrice Filippi, Royal Society (Mar 2017), £15,000
Ryan Seipke, BBSRC (Feb 2017), £52,116
Mary O'Connell, BBSRC (Feb 2017), £46,986
Hannah Dugdale, NERC (Feb 2017), £504,138
Anastasia Zhuravleva, EPSRC (Jan 2017), £100,792
Richard Bayliss, Cancer Research UK (Jan 2017), £1,600,000
John Barr, EU (Jan 2017), £339,000
Mark Harris, Royal Society (Jan 2017), £250,000
Alison Dunn, NERC (Jan 2017), £105,000
Alex Breeze, Pancreatic Cancer Research Fund (Jan 2017), £180,000
Alison Dunn, NERC (Dec 2016), £18,000
Lisa Collins, BBSRC (Dec 2016), £1,681,835
Brendan Davies, Leverhulme Trust (Dec 2016), £247,555
Alan Benson, Mark Drinkhill, Ed White, British Heart Foundaion (Dec 2016), £217,223
Adrian Goldman, Royal Society (Dec 2016), £82,999
Lisa Roberts, Alex Breeze, Brendan Davies, Timothy Devinney, Oliver Harlen, Joseph Holden, Anthea Hucklesby, Pamela Jones, Philip Mellor, RCUK (Nov 2016), £484,172
Lisa Roberts, Alex Breeze, Brendan Davies, Timothy Devinney, Oliver Harlen, Joseph Holden, Anthea Hucklesby, Pamela Jones, Philip Mellor, Wellcome Trust (Nov 2016), £119,343
Katie Field, Rank Prize Funds (Nov 2016), £20,000
Jessica Kwok, Royal Society (Nov 2016), £14,948
John Ladbury, Cancer Research UK (Oct 2016), £4,250
Miriam Wittmann, Martin Stacey, Edward Vital, Lupus UK
(Oct 2016), £34,010
Valerie Speirs, NC3Rs
(Oct 2016), £90,000
Nicola Stonehouse, Morgan Herod, David Rowlands, BBSRC
(Sep 2016), £436,424
Joseph Cockburn, Wellcome Trust
(Sep 2016), £100,000
John Barr, Public Health England
(Sep 2016), £94,471
Helen Miller, DSM Nutritional Products A/S
(Sep 2016), £54,680
Steven Clapcote, Vitaflo International Ltd
(Sep 2016), £39,285
Juan Fontana Jordan De Urries
, Royal Society
(Sep 2016), £21,793
Jing Li, Sarah Calaghan, Mark Drinkhill, British Heart Foundation
(Sep 2016), £117,585
Sheena Radford, Alison Ashcroft, BBSRC (Sep 2016), £457,216
Patricija Van Oosten-Hawle, An-Jung Chen, David Westhead, NC3Rs
(Sep 2016), £354,456
Glyn Hemsworth, BBSRC (Sep 2016), £1,024,034
David Jayne, Paul Millner, MRC (Aug 2016), £207,860
Sheena Radford, Alison Ashcroft, BBSRC (Aug 2016), £457,215
Patricija Van Oosten-Hawle, Dave Westhead, An-Jung Chen, NC3Rs (Aug 2016), £354,456
Peter Henderson, EU - European Union
EU - European Union
(Jul 2016), £123,897
Adrian Goldman, EU - European Union
(Jul 2016), £116,290
Urwin, Howard Atkinson, NERC
(Jul 2016), £105,053
Eileen Ingham and colleagues in Engineering and M&H, EPSRC (Jul 2016), £3,867,449
Michael Colman, MRC (Jul 2016), £200,956
Tim Benton, Fresca Group Ltd
(Jul 2016), £52,082