Advancing prostate cancer research with blood-based biomarkers
Published in Cancer and General & Internal Medicine
Metastatic prostate cancer (PCa) is associated with high morbidity and mortality rates 1. The response of metastatic PCa to the standard treatment options, such as androgen-deprivation therapy or metastasis-directed radiotherapy, is highly diverse, and more efficient tests are urgently warranted for predicting cancer spread and the response of PCa metastases to the treatment 2.
TGF-β1 plays a central role in PCa bone metastasis by promoting epithelial-to-mesenchymal transition (EMT), regulating matrix metalloproteinase (MMP) expression, and modulating interactions within the bone microenvironment, thereby facilitating tumor cell colonization and survival. Aldehyde dehydrogenase (ALDH) enzymes, crucial for cellular detoxification and cancer stem cell regulation, produce retinoic acid (RA) isomers that activate RAR and RXR nuclear receptors, triggering transcription of retinoid-responsive genes 3. TGF-β1 pathway regulates ALDH gene expression and cancer stem cell population 4, whereas RA interacts with TGF-β1 signaling in various cancers, suggesting a complex interplay between retinoid and TGF-β1 pathways 5.
Our study showed that ALDH1A1 and ALDH1A3, the main isoforms contributing to the ALDH activity in PCa cells, differentially regulate cell migration and TGFB1 expression depending on androgen receptor (AR) status. ALDH1A1 positively correlates with TGFB1 expression and promotes migration in androgen-sensitive cells, while ALDH1A3 has an opposing effect. Both ALDH genes regulate TGFB1 gene transcription through the RA-dependent mechanism. TGF-β1 pathway further contributes to the regulation of the MMP11 expression, which is associated with poor clinical outcomes in PCa. Genetic silencing of MMP11 increases tumor cell radiosensitivity, suggesting its role in therapy resistance. Indeed, MMP11 blood plasma levels had a significant association with PSA increase in patients with oligometastatic PCa treated with external beam radiotherapy. Moreover, plasma levels of MMP11 were significantly higher in patients with metastatic PCa compared to those with localized disease. MMP11 demonstrated potential as a blood-based biomarker for metastases, with high specificity (0.93) and sensitivity (0.9). Proteomic profiling identified an ALDH1A1/MMP11-related plasma proteome signature, which correlated with clinical outcomes (Figure 1).
Taken together, the study highlights the interplay between ALDH genes, TGF-β1, and MMP11 in PCa progression and metastasis. ALDH1A1-driven RA signaling promotes TGFB1 expression, which in turn regulates MMP11, contributing to metastatic dissemination and therapy resistance. Plasma MMP11 levels emerged as a promising prognostic biomarker for metastatic PCa. Our research marks a significant step in understanding PCa progression and highlights the potential of blood-based biomarkers like MMP11 for early detection of metastatic disease and personalized treatment strategies.
Figure 1. ALDH1A1 regulates TGFB1 expression in androgen-sensitive cells through AR- and RA-dependent mechanisms. In contrast, the interplay between TGF-β1 and MMP11 is present in the androgen-sensitive and castration-resistant models of PCa.
Lead authors of the study (from left to right): Anna Dubrovska, Ielizaveta Gorodetska.
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Journal of Experimental & Clinical Cancer Research
Journal of Experimental & Clinical Cancer Research is an online peer-reviewed journal that publishes original research papers, reviews and commentaries in cancer research, from bench to bedside.
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Insights into the relationship between metabolism and cancer
Cancer metabolism has become one of the most studied aspects of the "hallmarks of cancer." It refers to alterations in how tumor cells process nutrients to fuel their rapid proliferation and spread. These dramatic dysregulations include elevated glucose uptake even in the presence of oxygen (the Warburg effect), dependence on glutamine, and the production of waste products such as lactate, which further support tumor growth and metastasis. Genetic mutations accumulating during cancer progression in metabolic enzymes and cancer-promoting signaling pathways directly affect metabolic changes in cancer cells as well as in the tumor microenvironment [1,2].
A growing number of scientists are developing targeted therapies to exploit these metabolic differences to slow or halt cancer progression. Some therapies aim to block or alter the production of specific metabolites, while several drugs for other pathologies, such as diabetes, are of great interest due to their potential to slow tumor growth by altering systemic metabolic factors such as insulin and glucose levels in a "drug repositioning" strategy [3-7].
Cancer metabolism, involving altered lipid, iron, and amino acid pathways, regulates ferroptosis, an iron-dependent, lipid peroxidation-driven form of cell death. Cancer cells often resist this process, but targeting their specific metabolic vulnerabilities, such as glutathione depletion or iron overload, can trigger ferroptosis to kill tumor cells and overcome drug resistance [8].
Cancer cells can rewire their metabolism when one pathway is blocked, so it is becoming clear that combining metabolism inhibitors with traditional chemotherapy, radiotherapy, or immunotherapy may be an effective therapeutic strategy [8]. While some metabolism-targeting drugs have been successful (e.g., in Acute Lymphocytic Leukemia), targeting cancer metabolism is complex due to its similarity to normal cell processes [9]. Metabolic profiling of patients is helping to identify specific vulnerabilities, leading to more personalized metabolic therapies [10].
Understanding cancer metabolism at a deeper mechanistic level is also essential to improving immunotherapy, as immune cell metabolism changes during therapy administration, contributing to acquired resistance.
KEYWORDS: metabolomics; proteomics, genomics, mitochondrial metabolism, ferroptosis, oxidative stress, inflammation, innovative study models, new translational therapeutic approaches.
In this Collection of the Journal of Experimental & Clinical Cancer Research, we would like to promote studies that further dissect the molecular mechanisms through which cancer cells reprogram their own metabolism and that of cells in the tumor microenvironment, thus driving disease progression. Furthermore, studies that highlight potential metabolic vulnerabilities that could be targeted therapeutically will be of interest.
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