There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. The tumoral promoting effects of obesity occur locally through the inflammation of adipose tissue and the associated alterations in the microenvironment (2). Therefore, the characterization of biomarkers to identify patients with obesity with high-risk CRC seems of paramount in order to contribute to an early diagnosis and improvement in the election of the most appropriate therapeutic protocols.
In this context, considering that telomere shortening has been associated with obesity in several studies, and that telomere maintenance is critical for the progression of cancer, our study was carried out considering a large population of CRC patients, with and without obesity, submitted to surgery with curative intention. Results from this work allowed us to demonstrate that telomere status is related to obesity and clinical prognosis.
Although the activity of telomerase was positive in most of the tumors considered in our study, we detected a significant shortening of telomeres in the tumor samples compared to the mean values of the telomere length observed in the non-tumoral paired tissues, as previously reported by others (12, 25). Furthermore, according to the results obtained in the present investigation, the lower mean values of telomere length, both in tumors and in their non-tumoral paired tissues, were associated with earlier stages of Dukes, in agreement with other groups (26). Thus, these data prove that shorter telomeres are associated with cancers that, a priori, would confer a better prognosis to patients with CRC. In addition, our results indicate that cancers displaying lower values of shortening of telomere length, occur in patients with obesity. We consider these data of interest since, although several studies have established a link between obesity and the risk of colon cancer, little is known about the effect of obesity on the outcomes after diagnosis (7).
It has been reported that a BMI greater than 35.0 kg/m2 at the time of diagnosis in patients with colon cancer is associated with an increased risk of recurrence (7). However, other authors have not confirmed these data, nor a significant correlation between BMI and an increased risk of death in patients with CRC (27). It has also been suggested that BMI prior to diagnosis is an important predictor of survival among patients with non-metastatic CRC (6). More recently, Bhaskaran et al. have reported that heterogeneity in the effects of BMI suggests different mechanisms or combinations of mechanisms associated with different tumor locations and in different subgroups of patients (5).
In our study, the group of patients with BMI values greater than 31.85 kg/m2, showed a significantly worse clinical prognosis. However, Cox multivariate regression analyses did not demonstrate that these results were independent of the Dukes tumor stage.
Interestingly, our results indicate significant differences according to the gender: when the effect of obesity on the prognosis of patients with CRC was analyzed, these differences were only evident in the male population. Although this fact could be explained by considering the relationship between gender and fat distribution (28), other aspects might be further investigated, including additional genetic, hormonal or molecular mechanisms, in order to explain the effect of obesity on the prognosis of CRC related to the gender of patients (29).
With respect to the telomere status, our data support that the prognosis of patients with CRC, whether with or without obesity, is strongly related to the length of the tumor telomere, being these results independent of the stage of the tumor.
In the present study we have identified a specific length of telomere in non-tumoral tissues that seems critical to predict the prognosis of cancer. Therefore, patients with a telomere length less than 7.1 kb in non-tumoral tissues present a better clinical evolution, considering both subjects with and without obesity. At this point, our results would support the idea that carcinogenic cells have a common biological history with normal tissue (30).
These data allow us to hypothesize the possibility that tumor cells with shorter telomeres activate cellular senescence, thereby conferring a more favorable clinical prognosis to patients affected by CRC. In fact, the progressive shortening of telomeres results in the formation of dysfunctional telomeres that compromise tissue proliferation (15).
The shortening of human telomeres has two opposite effects during the development of cancer. On the one hand, the shortening of telomeres can exert a tumor suppressive effect through the arrest of proliferation. On the other hand, the loss of telomere protection can lead to a telomere crisis, which is a state of extensive genomic instability that can promote the progression of cancer (13). Our research team has previously reported data in CRC that support a worse clinical evolution in patients with maintenance of tumor telomeres (12).
In conclusion, in the present study we have jointly evaluated the prognostic relevance of obesity and telomere status in patients affected by CRC who had undergone surgery of curative intention. Our results demonstrate that the length of telomeres is a useful biomarker to predict the clinical outcome in these subjects. Patients with shorter telomeres, both in the tumoral and their non-tumoral paired tissues, had the best clinical evolution, independently of the Dukes' stage. Our data allow us to conclude that patients with obesity had a poorer prognosis, however, these results were not independent from the tumoral Dukes' stage.
Further investigations are needed to analyze the effect of obesity on the clinical course of CRC in the context of other factors, such as the gender of the patients.