We have shown in a previous report2
that those who are physically active prior to their diagnosis of CRC enjoy superior survival compared with those who are relatively inactive, and that this advantage remains after adjustment for standard prognostic indicators. This observation has contributed to the interest that has grown concerning possible links between cancer survival and both physical activity and adiposity. Associations have been observed in this regard not only for CRC 2,3
but also for breast19,20
cancer with the improvement in survival being a result of decreased cancer deaths rather than reduced deaths from cardiovascular disease.
In this report we have built on our previous finding by measuring IGF‐1 and IGFBP‐3 in plasma taken at recruitment to our cohort study some years before the subjects' diagnosis with CRC. We have shown that for people who are physically active, but not for those who are physically inactive, increasing plasma levels of IGFBP‐3, but not IGF‐1, are associated with improved survival from CRC. In addition, the previously reported benefit of regular physical activity was observed in cases with high but not low levels of IGFBP‐3 but was seen across all levels of IGF‐1. Together these results suggest a link between the improvement in cancer specific survival from exercise and circulating IGFBP‐3 levels.
The strengths of our study are its reasonable size, availability of plasma samples collected prior to diagnosis, standardised collection of epidemiological and clinical information, and completeness of follow up. Its limitations relate mainly to the fact that the assessment of both physical activity and IGF‐1/IGFBP‐3 levels occurred at a single point in time prior to the diagnosis of CRC. It is possible that the stronger associations we observed with IGFBP‐3 are because it was measured with less error, partly because it had less within person variability. We did not measure physical activity or plasma hormone levels following diagnosis and, therefore, cannot assess possible variations in either of these over the follow up period. We have however previously reported that the improved survival for the physically active was observed predominantly for stage II and III disease and was related to fewer recurrences, raising the possibility that increased physical activity may influence tumour behaviour and, in particular, metastatic potential.
One other study has attempted to assess the impact of the IGF axis on survival in patients diagnosed with CRC.22
This study assessed baseline IGF‐1 and IGFBP‐3 levels in 527 cases with metastatic CRC receiving palliative chemotherapy. Higher levels of IGFBP‐3 were associated with an increased response to chemotherapy, a longer time to progression, and improved overall survival. IGF‐1 was not related either to response, time to progression, or overall survival. This study supports our finding that IGFBP‐3 is more important than IGF‐1 to the prediction of outcome in CRC and may have prognostic significance.
Our current knowledge of the mechanism by which physical activity may positively influence the behaviour of cancers is poorly understood. IGF‐1 is central to the regulation of growth processes. In the circulation, over 90% of IGF‐1 is bound to IGFBP‐3 both of which are produced mainly in the liver. The main stimulus for IGF‐1 production comes from growth hormone.23
This stimulatory effect of growth hormone is modulated by insulin, which increases growth hormone receptor levels.24
In addition to increasing circulating IGF‐1, hyperinsulinaemia inhibits the synthesis of other IGF binding proteins.25
Studies have shown that, after binding to its receptors which are found on normal colonic mucosal cells as well as colon cancer cells, IGF‐1 can stimulate cell proliferation, inhibit apoptosis,26
and promote angiogenesis.27,28
On the other hand, IGFBP‐3 inhibits the action of IGF‐1 by limiting the availability of free hormone. IGFBP‐3 is also known to have actions independent of IGF‐1, including the ability to induce apoptosis (possibly via the tumour suppressor gene p‐53),29,30,31
and inhibit growth via the transforming growth factor β pathway.32
Our data suggest that these later factors are likely to be the most important because of the lack of an effect of IGF‐1 levels when corrected for IGFBP‐3 levels.
While it is well known that regular physical activity can decrease insulin resistance and, hence, serum insulin levels33
in addition to reducing adiposity, several studies have tried to assess the impact physical activity might have on the IGF axis, with mixed results. Some have shown little or no effect,34,35,36
while others have demonstrated reductions in IGF‐1 levels.37,38
Similarly, a clear relationship has not been demonstrated between physical activity and IGFBP‐3, with some studies showing elevated levels26,36,37
and others observing no change in levels.38,39
It is important to note that energy balance may play an important role in determining the response of the IGF axis to physical activity.40
Equally important is the timing of hormone measurement with respect to physical activity, with significant variations seen between measurement immediately following exercise and two or 48 hours later.36,40
In conclusion, we have shown an association between CRC specific survival and IGFBP‐3 levels in those who were physically active prior to diagnosis, with higher pre‐diagnosis levels of IGFBP‐3 resulting in a significantly lower risk of death. This association was not seen for those who were physically inactive prior to diagnosis nor was there any association seen between IGF‐1 and outcome, irrespective of physical activity. This study supports the hypothesis that the beneficial effects of physical activity in reducing CRC mortality may occur through interactions with the IGF axis and in particular IGFBP‐3.