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)
Stephen Muench with Glaxo SmithKline & UCB Celltech, BBSRC Industrial Partnership Award (Apr 2018), £480,225
Steve Clapcote, BBSRC (Apr 2018), £443,072
Helen Miller, Innovate UK (Apr 2018), £999,960
Elisabetta Groppelli, David Rowlands & Stanley Lemon (University of North Carolina), Medical Research Foundation Fellowship (Apr 2018), £293,494
Nikesh Patel, Medical Research Foundation fellowship (Apr 2018), £290,976
Graham Askew with colleagues in Hull and Liverpool, BBSRC (Apr 2018), £150,498
Andrew Macdonald, Neil Ranson & Richard Foster, Kidney Research UK (Apr 2018), £82,821
Jessica Kwok & Ralf Richter, Leverhulme Trust (Apr 2018), £298,273
Julie Aspden, Royal Society (Apr 2018), £20,000
Liz Duncan, Royal Society (Mar 2018), £14,602
Alex O'Neill & Ryan Seipke, BBSRC (Feb 2018), £45,489
Jim Deuchars, Royal Society (Feb 2018), £16,300
Stefan Kepinski & Netta Cohen, Leverhulme Trust (Feb 2018), £320,387
Lisa Collins, BBSRC (Feb 2018), £49,950
Alison Baker, BBSRC (Feb 2018), £30,000
Nikita Gamper, BBSRC (Feb 2018), £30,000
Lars Jeuken, BBSRC (Feb 2018), £30,000
Scott Bowen, Leducq Foundation Grant (Feb 2018), £28,470
Jessica Kwok and Ronaldo Ichiyama, International Spinal Research Trust (Feb 2018), £94,450
Alex O'Neill, Oxford Drug Design (Jan 2018), £86,098
Dave Lewis and Colleagues in South Africa, HEFCE Global Challenge Research (Jan 2018), £48,000
Sarah Calaghan, Ed White, John Colyer, Isuru Jayasinghe, BHF (Jan 2018), £128,308
Christine Foyer and Alison Baker, HEFCE GCRF Grant (Jan 2018), £71,158
Alison Baker, Yun Yung Gong and Lindsay Stringer and ICRISAT India, HEFCE GCRF Grant (Jan 2018), £27,000
Graham Askew, Simon Walker, BBSRC (Jan 2018), £699,781
Jennifer Tomlinson, Royal Society (Jan 2018), £512,801
Alison Dunn, NERC (Dec 2017), £18,000
Jennifer Tomlinson, Royal Society-Research Fellows Enhancement Award (Dec 2017), £94,681
Helen Miller, AB AGri Grant (Dec 2017), £73,600
Simon Walker, Royal Society Enhancement Award (Dec 2017), £10,000
Carrie Ferguson, Bryan Taylor, Harry Rossiter, The Physiological Society (Dec 2017), £7,392
Ralf Richter, Royal Society (Dec 2017), £6,000
Christine Foyer, British Council Newton Fund (Dec 2017), £49,840
Adrian Whitehouse and colleagues in School of Chemistry and University of Liverpool, MRC (Nov 2017), £622,319
Michelle Peckham, Neil Ransom, MRC (Nov 2017), £495,159
Dave Lewis, British Council India (Nov 2017), £22,540
Hannah Dugdale, Royal Society (Nov 2017), £15,000
Elton Zeqiraj, Royal Society (Nov 2017), £15,000
Shaunna Burke, Cancer Research UK Innovation Grant (Nov 2017), £20,000
Alex O'Neill and colleagues in Chemistry, BBSRC (Nov 2017), £431,865
Jessica Kwok, Wings for Life (Nov 2017), £87,365
Tom Bennett, BBSRC (Oct 2017), £523,679
Neil Ranson, Darren Tomlinson, BBSRC (Oct 2017), £494,318
Nikita Gamper, BBSRC (Oct 2017), £490,426
Amanda Bretman and colleagues from UEA, NERC (Oct 2017), £430,886
Juan Fontana, Rosetrees Trust consumables grant (Oct 2017), £22,500
Helen Miller, DSM Nutritional Products AG (Sep 2017), £69,988
Neil Ranson, Juan Fontana, Mark Harris, Michelle Peckham, Ralf Richter, Peter Stockley, Patricija Van Oosten-Hawle and colleagues in Engineering, FMH and MAPS, Wellcome Trust Equipment Call (Sep 2017), £418,000
Jamie Johnston, Physiological Society (Sep 2017), £10,000
Frank Sobott, Adrian Goldman, Mark Harris, Andrew Macdonald, Stephen Muench, Sheena Radford and colleagues in FMH and MAPS, Wellcome Trust Equipment Call (Aug 2017), £415,000
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