Browsing by Author "Linē, Aija"

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    Comprehensive characterization of RNA cargo of extracellular vesicles in breast cancer patients undergoing neoadjuvant chemotherapy
    (2022-10-26) Sadovska, Lilite; Zayakin, Pawel; Eglītis, Kristaps; Endzeliņš, Edgars; Radoviča-Spalviņa, Ilze; Avotiņa, Elīza; Auders, Jānis; Keiša, Laura; Liepniece-Karele, Inta; Leja, Mārcis; Eglītis, Jānis; Linē, Aija; Department of Pathology
    Extracellular vesicles (EVs) are g7aining increased attention as carriers of cancer-derived molecules for liquid biopsies. Here, we studied the dynamics of EV levels in the plasma of breast cancer (BC) patients undergoing neoadjuvant chemotherapy (NAC) and explored the relevance of their RNA cargo for the prediction of patients’ response to the therapy. EVs were isolated from serial blood samples collected at the time of diagnosis, at the end of NAC, and 7 days, 6, and 12 months after the surgery from 32 patients with locally advanced BC, and 30 cancer-free healthy controls (HCs) and quantified by nanoparticle tracking analysis. The pre-treatment levels of EVs in BC patients were higher than in HCs, significantly increased during the NAC and surgery, and decreased to the levels found in HCs 6 months after surgery, thus showing that a substantial fraction of plasma EVs in BC patients are produced due to the disease processes and treatment. RNA sequencing analysis revealed that the changes in the EV levels were associated with the alterations in the proportions of various RNA biotypes in EVs. To search for RNA biomarkers that predict response to the NAC, patients were dichotomized as responders and non-responders based on Miller-Payne grades and differential expression analyses were carried out between responders and non-responders, and HCs. This resulted in the identification of 6 miRNAs, 4 lncRNAs, and 1 snoRNA that had significantly higher levels in EVs from non-responders than responders at the time of diagnosis and throughout the NAC, and significantly lower levels in HCs, thus representing biomarkers for the prediction of response to NAC at the time of diagnosis. In addition, we found 14 RNAs representing piRNA, miRNA, lncRNA, snoRNA, and snRNA biotypes that were induced by NAC in non-responders and 2 snoRNAs and 1 piRNA that were induced by NAC in patients with early disease progression, thus warranting further functional studies on their role in chemoresistance and metastasis.
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    The Effect of High-Intensity Interval Training on Quality of Life and Incidence of Chemotherapy Side Effects in Women With Breast Cancer
    (2024-01-01) Kļaviņa, Aija; Cešeiko, Rūdolfs; Čampa, Mārtiņš; Jermoļenko, Grēta Frančeska; Eglītis, Kristaps; Llorente, Alicia; Linē, Aija; Latvian Academy of Sport Education (LASE); Rīga Stradiņš University
    UNLABELLED Women with breast cancer (BC) experience multiple symptoms related to neoadjuvant chemotherapy (NAC) treatment that impair their functioning and quality of life (QoL). This study aimed to explore the effect of high-intensity aerobic interval training (HIIT) on quality of life and NAC side effects in women with BC. METHODS 56 patients (48.56 (7.84) years, range 35-64 years) diagnosed locally advanced (stage II-III) ER + BC receiving doxorubicin/cyclophosphamide-based NAC were randomly assigned to the HIIT group and a control group (CG) for 6 months. The HIIT group performed 2 to 3 HIIT sessions per week according to the study protocol (4 × 4 minutes at 85%-95% peak heart rate (HR)). The CG followed the standard of care instructions by the oncologists. To assess the QoL participants completed the EORTC QLQ-C30 with the additional BC module of QLQ BR-23. Weekly self-reports on NAC side effects were collected through online survey. RESULTS Study data were analyzed for 37 participants (nHIIT = 17, nCON = 20) who reported at least 14 (60%) weeks. HIIT was effective to reduce BC symptom scale outcomes (ES = 0.113, P = .048), and alleviate systemic therapy side effects (ES = 0.154, P = .020) and cancer related symptoms (ES = 0.124, P = .038). The most common side effect participants experienced at least 1 to 4 days/week was pain (average 50.9% and 56.8% for HIIT and CG, respectively), followed by sleep disturbances (average 50.9% and 49.9%, respectively). About 31% in both groups experienced sleep disturbances 5 to 7 days/week. The NAC induced physical, social and fatigue side effects had significantly lower incidence in HIIT group, while psychological side effects were significantly more common in training group. CONCLUSIONS HIIT is an effective physical exercise program to maintain higher quality of life and help to reduce some of NAC induced side effects for women with BC.
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    Effects of urinary extracellular vesicles from prostate cancer patients on the transcriptomes of cancer-associated and normal fibroblasts
    (2022-12) Sadovska, Lilite; Zayakin, Pawel; Bajo-Santos, Cristina; Endzeliņš, Edgars; Auders, Jānis; Keiša, Laura; Jansons, Juris; Lietuvietis, Vilnis; Linē, Aija; Rīga Stradiņš University
    Background: Increasing evidence suggests that cancer-derived extracellular vesicles (EVs) alter the phenotype and functions of fibroblasts and trigger the reprogramming of normal fibroblasts into cancer-associated fibroblasts (CAFs). Here, we for the first time studied the effects of urinary EVs from PC patients and healthy males on the transcriptional landscape of prostate CAFs and normal foreskin fibroblasts. Methods: Patient-derived prostate fibroblast primary cultures PCF-54 and PCF-55 were established from two specimens of PC tissues. EVs were isolated from urine samples of 3 patients with PC and 2 healthy males and used for the treatment of prostate fibroblast primary cultures and normal foreskin fibroblasts. The EV-treated fibroblasts were subjected to RNA sequencing analysis. Results: RNA sequencing analysis showed that the fibroblast cultures differed significantly in their response to urinary EVs. The transcriptional response of foreskin fibroblasts to the urinary EVs isolated from PC patients and healthy controls was very similar and mostly related to the normal functions of fibroblasts. On the contrary, PCF-54 cells responded very differently - EVs from PC patients elicited transcriptional changes related to the regulation of the cell division and chromosome segregation, whereas EVs from healthy males affected mitochondrial respiration. In PCF-55 cells, EVs from both, PC-patients and controls induced the expression of a number of chemokines such as CCL2, CCL13, CXCL1, CXCL8, whereas pathways related to regulation of apoptotic signaling and production of cell adhesion molecules were triggered specifically by EVs from PC patients. Conclusion: This study demonstrates that urinary EVs from PC patients and healthy controls elicit distinct transcriptional responses in prostate CAFs and supports the idea that EVs contribute to the generation of functional heterogeneity of CAFs. Moreover, this study suggests that the changes in the gene expression pattern in EV recipient cells might serve as a novel type of functional cancer biomarkers.
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    Extracellular Vesicles—A Source of RNA Biomarkers for the Detection of Breast Cancer in Liquid Biopsies
    (2023-09) Zayakin, Pawel; Sadovska, Lilite; Eglītis, Kristaps; Romanchikova, Nadezhda; Radoviča-Spalviņa, Ilze; Endzeliņš, Edgars; Liepniece-Karele, Inta; Eglītis, Jānis; Linē, Aija; Department of Pathology
    Over the past decade, extracellular vesicles (EVs) have emerged as a promising source of cancer-derived RNAs for liquid biopsies. However, blood contains a pool of heterogeneous EVs released by a variety of cell types, making the identification of cancer RNA biomarkers challenging. Here, we performed deep sequencing of plasma EV RNA cargo in 32 patients with locally advanced breast cancer (BC) at diagnosis and 7 days after breast surgery and in 30 cancer-free healthy controls (HCs). To identify BC-derived RNA biomarkers, we searched for RNAs that had higher levels in BC EVs at the time of diagnosis compared with HCs and decreased after surgery. Data analysis showed that the fractions of miRNAs, snRNAs, snoRNAs, and tRFs were increased, but the fraction of lncRNAs was decreased in BC EVs as compared to HCs. BC-derived biomarker candidates were identified across various RNA biotypes. Considered individually, they had very high specificity but moderate sensitivity for the detection of BC, whereas a biomarker model composed of eight RNAs: SNORD3H, SNORD1C, SNORA74D, miR-224-5p, piR-32949, lnc-IFT-122-2, lnc-C9orf50-4, and lnc-FAM122C-3 was able to distinguish BC from HC EVs with an AUC of 0.902 (95% CI = 0.872–0.931, p = 3.4 × 10−9) in leave-one-out cross-validation. Furthermore, a number of RNA biomarkers were correlated with the ER and HER2 expression and additional biomarker models were created to predict hormone receptor and HER2 status. Overall, this study demonstrated that the RNA composition of plasma EVs is altered in BC patients and that they contain cancer-derived RNA biomarkers that can be used for BC detection and monitoring using liquid biopsies.
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    From sweat to hope : The role of exercise-induced extracellular vesicles in cancer prevention and treatment
    (2024-08) Llorente, Alicia; Brokāne, Agnese; Mlynska, Agata; Puurand, Marju; Sagini, Krizia; Folkmane, Signe; Hjorth, Marit; Martin-Gracia, Beatriz; Romero, Silvana; Skorinkina, Diana; Čampa, Mārtiņš; Cešeiko, Rūdolfs; Romanchikova, Nadezhda; Kļaviņa, Aija; Käämbre, Tuuli; Linē, Aija; Rīga Stradiņš University; Latvian Academy of Sport Education (LASE)
    The benefits of regular physical exercise on cancer prevention, as well as reducing fatigue, treatment side effects and recurrence, and improving quality of life and overall survival of cancer patients, are increasingly recognised. Initial studies showed that the concentration of extracellular vesicles (EVs) increases during physical activity and that EVs carry biologically active cargo. These EVs are released by blood cells, skeletal muscle and other organs involved in exercise, thus suggesting that EVs may mediate tissue crosstalk during exercise. This possibility triggered a great interest in the study of the roles of EVs in systemic adaptation to exercise and in their potential applications in the prevention and treatment of various diseases, including cancer. This review presents studies exploring the concentration and molecular cargo of EVs released during exercise. Furthermore, we discuss putative stimuli that may trigger EV release from various cell types, the biological functions and the impact of exercise-induced EVs on cancer development and progression. Understanding the interplay between exercise, EVs, and cancer biology may offer insights into novel therapeutic strategies and preventive measures for cancer.
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    Plasma and urinary extracellular vesicles as a source of RNA biomarkers for prostate cancer in liquid biopsies
    (2023-02-03) Bajo-Santos, Cristina; Brokāne, Agnese; Zayakin, Pawel; Endzeliņš, Edgars; Soboļevska, Kristīne; Belovs, Alberts; Jansons, Juris; Sperga, Māris; Llorente, Alicia; Radoviča-Spalviņa, Ilze; Lietuvietis, Vilnis; Linē, Aija; Rīga Stradiņš University
    Introduction: Extracellular vesicles (EVs) have emerged as a very attractive source of cancer- derived RNA biomarkers for the early detection, prognosis and monitoring of various cancers, including prostate cancer (PC). However, biofluids contain a mixture of EVs released from a variety of tissues and the fraction of total EVs that are derived from PC tissue is not known. Moreover, the optimal biofluid—plasma or urine—that is more suitable for the detection of EV- enclosed RNA biomarkers is not yet clear. Methodology: In the current study, we performed RNA sequencing analysis of plasma and urinary EVs collected before and after radical prostatectomy, and matched tumor and normal prostate tissues of 10 patients with prostate cancer. Results and Discussion: The most abundant RNA biotypes in EVs were miRNA, piRNA, tRNA, lncRNA, rRNA and mRNA. To identify putative cancer-derived RNA biomarkers, we searched for RNAs that were overexpressed in tumor as compared to normal tissues, present in the pre-operation EVs and decreased in the post-operation EVs in each RNA biotype. The levels of 63 mRNAs, 3 lncRNAs, 2 miRNAs and 1 piRNA were significantly increased in the tumors and decreased in the post-operation urinary EVs, thus suggesting that these RNAs mainly originate from PC tissue. No such RNA biomarkers were identified in plasma EVs. This suggests that the fraction of PC-derived EVs in urine is larger than in plasma and allows the detection and tracking of PC-derived RNAs.
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    Validation of potential RNA biomarkers for prostate cancer diagnosis and monitoring in plasma and urinary extracellular vesicles
    (2023-11-30) Brokāne, Agnese; Bajo-Santos, Cristina; Zayakin, Pawel; Belovs, Alberts; Jansons, Juris; Lietuvietis, Vilnis; Martens-Uzunova, Elena S.; Jenster, Guido W.; Linē, Aija; Rīga Stradiņš University
    Introduction: Prostate cancer (PCa), one of the most prevalent malignancies affecting men worldwide, presents significant challenges in terms of early detection, risk stratification, and active surveillance. In recent years, liquid biopsies have emerged as a promising non-invasive approach to complement or even replace traditional tissue biopsies. Extracellular vesicles (EVs), nanosized membranous structures released by various cells into body fluids, have gained substantial attention as a source of cancer biomarkers due to their ability to encapsulate and transport a wide range of biological molecules, including RNA. In this study, we aimed to validate 15 potential RNA biomarkers, identified in a previous EV RNA sequencing study, using droplet digital PCR. Methods: The candidate biomarkers were tested in plasma and urinary EVs collected before and after radical prostatectomy from 30 PCa patients and their diagnostic potential was evaluated in a test cohort consisting of 20 benign prostate hyperplasia (BPH) and 20 PCa patients’ plasma and urinary EVs. Next, the results were validated in an independent cohort of plasma EVs from 31 PCa and 31 BPH patients. Results: We found that the levels of NKX3-1 (p = 0.0008) in plasma EVs, and tRF-Phe-GAA-3b (p < 0.0001) tRF-Lys-CTT-5c (p < 0.0327), piR-28004 (p = 0.0081) and miR-375-3p (p < 0.0001) in urinary EVs significantly decreased after radical prostatectomy suggesting that the main tissue source of these RNAs is prostate and/or PCa. Two mRNA biomarkers—GLO1 and NKX3-1 showed promising diagnostic potential in distinguishing between PCa and BPH with AUC of 0.68 and 0.82, respectively, in the test cohort and AUC of 0.73 and 0.65, respectively, in the validation cohort, when tested in plasma EVs. Combining these markers in a biomarker model yielded AUC of 0.85 and 0.71 in the test and validation cohorts, respectively. Although the PSA levels in the blood could not distinguish PCa from BPH in our cohort, adding PSA to the mRNA biomarker model increased AUC from 0.71 to 0.76. Conclusion: This study identified two novel EV-enclosed RNA biomarkers–NKX3-1 and GLO1–for the detection of PCa, and highlights the complementary nature of GLO1, NKX3-1 and PSA as combined biomarkers in liquid biopsies of PCa.