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Authors
Abstract(s)
The worldwide social and economic impact of cancer keeps increasing and proper disease management is a critical step to reducing the cancer burden on society, where appropriate diagnosis, staging, and treatment are key factors. Concomitantly, the increasing prevalence of obesity brings forward its importance as a risk factor for cancer development but also allows to explore associated metabolites and signaling pathways as tools for cancer research. As such, the studies presented in this thesis aim to tackle two pillars in cancer research: early diagnosis and therapy resistance, by exploring metabolism-related hormones as disease biomarkers and their impact on resistance to chemoradiotherapy, as well as unraveling novel molecules targeting cancer stem cells as major culprits in refractory cancer.
In our first study, we focused on nonalcoholic fatty liver disease (NAFLD) as a predisposing risk factor for the development of hepatocellular carcinoma. Our goal was to evaluate serum levels of metabolism hormones as non-invasive biomarkers aiming to produce diagnostic options alternative to liver biopsy. Using two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls, we measured adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) serum levels. Leptin serum levels were able to discriminate NAFLD with obesity posing as a potential confounding factor. Adiponectin serum levels combined with specific serum lipids composed a biomarker panel with good assay performance for the stratification of nonalcoholic steatohepatitis versus nonalcoholic fatty liver, however, it can be influenced by the presence of patatin-like phosphate domain-containing protein 3 (PNPLA3) genetic polymorphisms. In turn, IGF-1 levels combined with INR and ferritin were able to distinguish advanced liver fibrosis outranking other fibrosis evaluation scores used in the clinical practice.
Next, we followed to evaluate how adiponectin and leptin modulated cell stemness and influenced resistance to chemoradiotherapy in rectal cancer patients, and ultimately providing novel biomarker candidates to identify patients not responding to neoadjuvant therapy. By evaluating serum and biopsy tissue from a cohort of locally advanced rectal cancer, we observed that leptin and adiponectin serum levels were not able to identify non-responder patients to chemoradiotherapy. Yet, high leptin and low adiponectin levels were associated with worsened clinical outcomes and unfavorable patient survival. At a molecular level, leptin serum profile was associated with increased expression of Yamanaka factors mRNA, particularly of octamer-binding transcription factor 4 (OCT4) and Kruppel-like factor 4 (KLF4), as well as signal transducer and activator of transcription 3 (STAT3) activation in the biopsy tissues, and all three parameters tended to increase in non-responders. Bringing together STAT3 activation, OCT4, and KLF4 mRNA expression with carcinoembryonic antigen levels – the only serological parameter that distinguished responders from non-responders – we were able to establish a high-performance biomarker panel to distinguish rectal cancer patient responders versus non-responders to chemoradiotherapy.
In our third study, we focused on cancer stem cells as a cause of cancer relapse and resistance to therapy. Taking advantage of in vitro tumorsphere forming assays, we identified a curcumin analog that was able to reduce cellular viability of several colorectal cancer cell lines, by modulating stemness traits and inducing apoptosis. Importantly, this compound significantly reduced tumor burden in an in vivo xenograft mouse model following the same mechanisms of action. Moreover, in silico analysis identified nuclear factor kappa B (NF-ĸB) and STAT3 as putative molecular targets that were later confirmed both in vitro and in vivo.
In conclusion, our studies highlight how hormones associated with obesity may pose as biomarkers in chronic disease diagnosis and valuable tools in cancer prognosis. Moreover, our results support the influence of obesity on cancer development and clinical outcome, and how its associated signaling pathways provide valuable targets for an innovative approach developed to treat cancer. Finally, we discovered a novel molecule that by targeting those signaling pathways could be a promising drug candidate for therapy insensitive tumors.
Description
Keywords
Adipoquinas Biomarcadores Células estaminais cancerígenas Cancro do trato gastrointestinal Resistência à terapêutica Adipokines Biomarker Cancer stem cells Gastrointestinal tract cancer Resistance to therapy