Browsing by Subject "TUMOR"

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  • Barmaki, Samineh; Jokinen, Ville; Obermaier, Daniela; Blokhina, Daria; Korhonen, Matti; Ras, Robin H. A.; Vuola, Jyrki; Franssila, Sami; Kankuri, Esko (2018)
    Physiological oxygen levels within the tissue microenvironment are usually lower than 14%, in stem cell niches these levels can be as low as 0-1%. In cell cultures, such low oxygen levels are usually mimicked by altering the global culture environment either by O-2 removal (vacuum or oxygen absorption) or by N-2 supplementation for O-2 replacement. To generate a targeted cellular hypoxic microenvironment under ambient atmospheric conditions, we characterised the ability of the dissolved oxygen-depleting sodium sulfite to generate an in-liquid oxygen sink. We utilised a microfluidic design to place the cultured cells in the vertical oxygen gradient and to physically separate the cells from the liquid. We demonstrate generation of a chemical in-liquid oxygen sink that modifies the surrounding O-2 concentrations. O-2 level control in the sink-generated hypoxia gradient is achievable by varying the thickness of the polydimethylsiloxane membrane. We show that intracellular hypoxia and hypoxia response element-dependent signalling is instigated in cells exposed to the microfluidic in-liquid O-2 sink-generated hypoxia gradient. Moreover, we show that microfluidic flow controls site-specific microenvironmental kinetics of the chemical O-2 sink reaction, which enables generation of intermittent hypoxia/re-oxygenation cycles. The microfluidic O-2 sink chip targets hypoxia to the cell culture microenvironment exposed to the microfluidic channel architecture solely by depleting O-2 while other sites in the same culture well remain unaffected. Thus, responses of both hypoxic and bystander cells can be characterised. Moreover, control of microfluidic flow enables generation of intermittent hypoxia or hypoxia/re-oxygenation cycles. (C) 2018 Published by Elsevier Ltd on behalf of Acta Materialia Inc.
  • Farnebo, Lovisa; Laurell, Goran; Makitie, Antti (2016)
    Conclusion: The management of Head and Neck Cancer of Unknown Primary (HNCUP) patients varies both between centres within and also between the Nordic countries. This study contributes to a continuing discussion of how to improve the accuracy of diagnosis and quality of treatment of HNCUP patients.Objectives: The initiative for this study was based on the lack of common guidelines for diagnostic procedures and for treatment of HNCUP patients in the Nordic countries constituting a region having a rather homogeneous population.Method: A structured questionnaire was sent to all university hospitals in the five Nordic countries.Results: Four of the five Nordic countries use either national guidelines or specific protocols when handling HNCUP. The main diagnostic tools are PET-CT, fine needle aspiration, endoscopic evaluation with biopsies, and most often bilateral tonsillectomy. At 21 of 22 university hospitals the treatment decision is made at a multidisciplinary conference. Three of seven Swedish centres use only radiotherapy or chemoradiotherapy to treat N+ HNCUP patients. Robotic surgery for biopsy of the tongue base is beginning to become an alternative to targeted biopsies in Sweden and Finland. Narrow Band Imaging is used only in Finland.
  • Sinha, Snehadri; Narjus-Sterba, Matilda; Tuomainen, Katja; Kaur, Sippy; Seppänen-Kaijansinkko, Riitta; Salo, Tuula; Mannerström, Bettina; Al-Samadi, Ahmed (2020)
    Mesenchymal stem cells (MSCs) are commonly isolated from bone marrow and adipose tissue. Depending on the tissue of origin, MSCs have different characteristics and physiological effects. In various cancer studies, MSCs have been found to have either tumor-promoting or tumor-inhibiting action. This study investigated the effect of adipose tissue-MSCs (AT-MSCs) and bone marrow-MSCs (BM-MSCs) on global long interspersed nuclear element-1 (LINE-1) methylation, the expression level of microenvironment remodeling genes and cell proliferation, migration and invasion of oral tongue squamous cell carcinoma (OTSCC). Additionally, we studied the effect of human tongue squamous carcinoma (HSC-3)-conditioned media on LINE-1 methylation and the expression of microenvironment remodeling genes in AT-MSCs and BM-MSCs. Conditioned media from HSC-3 or MSCs did not affect LINE-1 methylation level in either cancer cells or MSCs, respectively. In HSC-3 cells, no effect of MSCs-conditioned media was detected on the expression ofICAM1, ITGA3orMMP1. On the other hand, HSC-3-conditioned media upregulatedICAM1andMMP1expression in both types of MSCs. Co-cultures of AT-MSCs with HSC-3 did not induce proliferation, migration or invasion of the cancer cells. In conclusion, AT-MSCs, unlike BM-MSCs, seem not to participate in oral cancer progression.
  • Eloranta, Katja; Cairo, Stefano; Liljeström, Emmi; Soini, Tea; Kyrönlahti, Antti; Judde, Jean-Gabriel; Wilson, David B.; Heikinheimo, Markku; Pihlajoki, Marjut (2020)
    Background:Hepatoblastoma (HB) is the most common pediatric liver malignancy. Despite advances in chemotherapeutic regimens and surgical techniques, the survival of patients with advanced HB remains poor, underscoring the need for new therapeutic approaches. Chloroquine (CQ), a drug used to treat malaria and rheumatologic diseases, has been shown to inhibit the growth and survival of various cancer types. We examined the antineoplastic activity of CQ in cell models of aggressive HB. Methods:Seven human HB cell models, all derived from chemoresistant tumors, were cultured as spheroids in the presence of relevant concentrations of CQ. Morphology, viability, and induction of apoptosis were assessed after 48 and 96 h of CQ treatment. Metabolomic analysis and RT-qPCR based Death Pathway Finder array were used to elucidate the molecular mechanisms underlying the CQ effect in a 2-dimensional cell culture format. Quantitative western blotting was performed to validate findings at the protein level. Results:CQ had a significant dose and time dependent effect on HB cell viability both in spheroids and in 2-dimensional cell cultures. Following CQ treatment HB spheroids exhibited increased caspase 3/7 activity indicating the induction of apoptotic cell death. Metabolomic profiling demonstrated significant decreases in the concentrations of NAD(+)and aspartate in CQ treated cells. In further investigations, oxidation of NAD(+)decreased as consequence of CQ treatment and NAD(+)/NADH balance shifted toward NADH. Aspartate supplementation rescued cells from CQ induced cell death. Additionally, downregulated expression of PARP1 and PARP2 was observed. Conclusions:CQ treatment inhibits cell survival in cell models of aggressive HB, presumably by perturbing NAD(+)levels, impairing aspartate bioavailability, and inhibiting PARP expression. CQ thus holds potential as a new agent in the management of HB.
  • Sahu, Biswajyoti; Pihlajamaa, Päivi; Zhang, Kaiyang; Palin, Kimmo; Ahonen, Saija; Cervera, Alejandra; Ristimäki, Ari; Aaltonen, Lauri A.; Hautaniemi, Sampsa; Taipale, Jussi (2021)
    Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.
  • Hohtari, Helena; Bruck, Oscar; Blom, Sami; Turkki, Riku; Sinisalo, Marjatta; Kovanen, Panu E.; Kallioniemi, Olli; Pellinen, Teijo; Porkka, Kimmo; Mustjoki, Satu (2019)
    As novel immunological treatments are gaining a foothold in the treatment of acute lymphoblastic leukemia (ALL), it is elemental to examine ALL immunobiology in more detail. We used multiplexed immunohistochemistry (mIHC) to study the immune contexture in adult precursor B cell ALL bone marrow (BM). In addition, we developed a multivariate risk prediction model that stratified a poor survival group based on clinical parameters and mIHC data. We analyzed BM biopsy samples of ALL patients (n = 52) and healthy controls (n = 14) using mIHC with 30 different immunophenotype markers and computerized image analysis. In ALL BM, the proportions of M1-like macrophages, granzyme B+CD57+CD8+ T cells, and CD27+ T cells were decreased, whereas the proportions of myeloid-derived suppressor cells and M2-like macrophages were increased. Also, the expression of checkpoint molecules PD1 and CTLA4 was elevated. In the multivariate model, age, platelet count, and the proportion of PD1+TIM3+ double-positive CD4+ T cells differentiated a poor survival group. These results were validated by flow cytometry in a separate cohort (n = 31). In conclusion, the immune cell contexture in ALL BM differs from healthy controls. CD4+PD1+TIM3+ T cells were independent predictors of poor outcome in our multivariate risk model, suggesting that PD1 might serve as an attractive immuno-oncological target in B-ALL.
  • Korvala, Johanna; Jee, Kowan; Porkola, Emmi; Almangush, Alhadi; Mosakhani, Neda; Bitu, Carolina; Cervigne, Nilva K.; Zandonadi, Flavia S.; Meirelles, Gabriela V.; Paes Leme, Adriana Franco; Coletta, Ricardo D.; Leivo, Ilmo; Salo, Tuula (2017)
    Complex molecular pathways regulate cancer invasion. This study overviewed proteins and microRNAs (miRNAs) involved in oral tongue squamous cell carcinoma (OTSCC) invasion. The human highly aggressive OTSCC cell line HSC-3 was examined in a 3D organotypic human leiomyoma model. Non-invasive and invasive cells were laser-captured and protein expression was analyzed using mass spectrometry-based proteomics and miRNA expression by microarray. In functional studies the 3D invasion assay was replicated after silencing candidate miRNAs, miR-498 and miR-940, in invasive OTSCC cell lines (HSC-3 and SCC-15). Cell migration, proliferation and viability were also studied in the silenced cells. In HSC-3 cells, 67 proteins and 53 miRNAs showed significant fold-changes between non-invasive vs. invasive cells. Pathway enrichment analyses allocated "Focal adhesion" and "ECM-receptor interaction" as most important for invasion. Significantly, in HSC-3 cells, miR-498 silencing decreased the invasion area and miR-940 silencing reduced invasion area and depth. Viability, proliferation and migration weren't significantly affected. In SCC-15 cells, down-regulation of miR-498 significantly reduced invasion and migration. This study shows HSC-3 specific miRNA and protein expression in invasion, and suggests that miR-498 and miR-940 affect invasion in vitro, the process being more influenced by mir-940 silencing in aggressive HSC-3 cells than in the less invasive SCC-15.
  • Gao, Yan; Tong, Haibei; Li, Jialiang; Li, Jiachen; Huang, Di; Shi, Jisen; Xia, Bing (2021)
    Nanomedicines have been designed and developed to deliver anticancer drugs or exert anticancer therapy more selectively to tumor sites. Recent investigations have gone beyond delivering drugs to tumor tissues or cells, but to intracellular compartments for amplifying therapy efficacy. Mitochondria are attractive targets for cancer treatment due to their important functions for cells and close relationships to tumor occurrence and metastasis. Accordingly, multifunctional nanoplatforms have been constructed for cancer therapy with the modification of a variety of mitochondriotropic ligands, to trigger the mitochondria-mediated apoptosis of tumor cells. On this basis, various cancer therapeutic modalities based on mitochondria-targeted nanomedicines are developed by strategies of damaging mitochondria DNA (mtDNA), increasing reactive oxygen species (ROS), disturbing respiratory chain and redox balance. Herein, in this review, we highlight mitochondria-targeted cancer therapies enabled by nanoplatforms including chemotherapy, photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT) and combined immunotherapy, and discussed the ongoing challenges.
  • Youssef, Omar; Almangush, Alhadi; Zidi, Yossra H. S.; Loukola, Anu; Carpen, Olli (2020)
    Background:Archived formalin-fixed paraffin-embedded (FFPE) specimens from nonmalignant tissues derived from cancer patients are a vast and potentially valuable resource for high-quality genotyping analyses and could have a role in establishing inherited cancer risk. Methods:We systematically searched PubMed, Ovid MEDLINE, and Scopus databases for all articles that compared genotyping performance of DNA from nonmalignant FFPE tissue with blood DNA derived from cancer patients irrespective of tumor type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies, and extracted genotyping data from the eligible studies. These studies included, but were not limited to, genotyping technique, reported call rate, and concordance. Results:Thirteen studies were reviewed, in which DNA from nonmalignant FFPE tissues derived from cancer patients was successfully purified and genotyped. All these studies used different approaches for genotyping of DNA from nonmalignant FFPE tissues to amplify single nucleotide polymorphisms (SNPs) and to estimate of loss of heterozygosity. The concordance between genotypes from nonmalignant FFPE tissues and blood derived from cancer patients was observed to be high, whereas the call rate of the tested SNPs was not reported in all included studies. Conclusion:This review illustrates that DNA from nonmalignant FFPE tissues derived from cancer patients can serve as an alternative and reliable source for assessment of germline DNA for various purposes, including assessment of cancer predisposition.
  • Tervonen, Topi A.; Pant, Shishir M.; Belitskin, Denis; Englund, Johanna I.; Närhi, Katja; Haglund, Caj; Kovanen, Panu E.; Verschuren, Emmy W.; Klefström, Juha (2021)
    Ras proteins play a causal role in human cancer by activating multiple pathways that promote cancer growth and invasion. However, little is known about how Ras induces the first diagnostic features of invasion in solid tumors, including loss of epithelial integrity and breaching of the basement membrane (BM). In this study, we found that oncogenic Ras strongly promotes the activation of hepsin, a member of the hepsin/TMPRSS type II transmembrane serine protease family. Mechanistically, the Ras-dependent hepsin activation was mediated via Raf-MEK-ERK signaling, which controlled hepsin protein stability through the heat shock transcription factor-1 stress pathway. In Ras-transformed three-dimensional mammary epithelial culture, ablation of hepsin restored desmosomal cell-cell junctions, hemidesmosomes, and BM integrity and epithelial cohesion. In tumor xenografts harboring mutant KRas, silencing of hepsin increased local invasion concomitantly with accumulation of collagen IV. These findings suggest that hepsin is a critical protease for Ras-dependent tumorigenesis, executing cell-cell and cell-matrix pathologies important for early tumor dissemination. Significance: These findings identify the cell-surface serine protease hepsin as a potential therapeutic target for its role in oncogenic Ras-mediated deregulation of epithelial cell-cell and cell-matrix interactions and cohesion of epithelial structure.
  • Tamminen, Anselm; Meretoja, Tuomo; Koskivuo, Ilkka (2022)
    Introduction: Skin-sparing mastectomy (SSM) with immediate breast reconstruction is the ideal treatment for interested and suitable patients with extensive ductal carcinoma in situ (DCIS). There is no guideline to indicate on how large DCIS the procedure can be performed safely. The primary target of this study was to define the oncological safety of SSM in extensive pure DCIS. The secondary target was to find predictive factors for DCIS upstaging to invasive disease.Materials and methods: A total of 71 consecutive patients with extensive pure DCIS and undergoing SSM with immediate latissimus dorsi (LD) breast reconstruction were retrospectively evaluated. Results: The median size of DCIS lesion in preoperative imaging was 60 mm, the median weight of mastectomy specimen was 350 g, and the median resection margin (RM) was 2.0 mm. A total of 20 patients (28%) had an RM less than 0.5 mm and nine patients (13%) had ink positive margins. Six patients having positive RM underwent reoperation. A total of 29 patients (41%) presented invasive cancer foci in final histopathological assessment and nine patients (13%) had an axillary metastasis. Adjuvant therapy was given to 23 patients presenting invasive cancer. There were no local recurrences or distant metastases (0%, 95% confidence interval 0-0.051) during the mean follow-up of 71 mo. None of the factors evaluated predicted upstaging to invasive disease.Conclusions: SSM with immediate breast reconstruction in patients with extensive DCIS is oncologically safe even when the margins are close or positive. Additional invasive foci and solitary axillary lymph node metastases are frequent but do not worsen the outcome. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (
  • Mäkinen, Lotta; Vähä-Koskela, Markus; Juusola, Matilda; Mustonen, Harri; Wennerberg, Krister; Hagström, Jaana; Puolakkainen, Pauli; Seppänen, Hanna (2022)
    Simple Summary New treatments are urgently needed for pancreatic ductal adenocarcinoma because it is one of the most aggressive and lethal cancers, detected too late and resistant to conventional chemotherapy. Tumors in most patients feature a similar set of core mutations but so far it has not been possible to design a one-fits-all treatment strategy. Instead, efforts are underway to personalize the therapies. To find the treatments that might work the best for each patient, entirely new experimental platforms based on living miniature tumors, organoids, have been developed. We review here the latest international findings in designing personalized treatments pancreatic cancer patients using organoids as testing beds. Our own work adds important clues about how such testing could, and perhaps should, be conducted. Pancreatic ductal adenocarcinoma (PDAC) is a silent killer, often diagnosed late. However, it is also dishearteningly resistant to nearly all forms of treatment. New therapies are urgently needed, and with the advent of organoid culture for pancreatic cancer, an increasing number of innovative approaches are being tested. Organoids can be derived within a short enough time window to allow testing of several anticancer agents, which opens up the possibility for functional precision medicine for pancreatic cancer. At the same time, organoid model systems are being refined to better mimic the cancer, for example, by incorporation of components of the tumor microenvironment. We review some of the latest developments in pancreatic cancer organoid research and in novel treatment design. We also summarize our own current experiences with pancreatic cancer organoid drug sensitivity and resistance testing (DSRT) in 14 organoids from 11 PDAC patients. Our data show that it may be necessary to include a cell death read-out in ex vivo DSRT assays, as metabolic viability quantitation does not capture actual organoid killing. We also successfully adapted the organoid platform for drug combination synergy discovery. Lastly, live organoid culture 3D confocal microscopy can help identify individual surviving tumor cells escaping cell death even during harsh combination treatments. Taken together, the organoid technology allows the development of novel precision medicine approaches for PDAC, which paves the way for clinical trials and much needed new treatment options for pancreatic cancer patients.
  • Seppälä, Toni T.; Zimmerman, Jacquelyn W.; Sereni, Elisabetta; Plenker, Dennis; Suri, Reecha; Rozich, Noah; Blair, Alex; Thomas, Dwayne L.; Teinor, Jonathan; Javed, Ammar; Patel, Hardik M; Cameron, John L.; Burns, William R.; He, Jin; Tuveson, David A.; Jaffee, Elizabeth M.; Eshleman, James R; Szabolcs, Annamaria; Ryan, David P.; Ting, David T.; Wolfgang, Christopher L.; Burkhart, Richard A. (2020)
    Objective: PDAC patients who undergo surgical resection and receive effective chemotherapy have the best chance of long-term survival. Unfortunately, we lack predictive biomarkers to guide optimal systemic treatment. Ex-vivo generation of PDO for pharmacotyping may serve as predictive biomarkers in PDAC. The goal of the current study was to demonstrate the clinical feasibility of a PDO-guided precision medicine framework of care. Methods: PDO cultures were established from surgical specimens and endoscopic biopsies, expanded in Matrigel, and used for high-throughput drug testing (pharmacotyping). Efficacy of standard-of-care chemotherapeutics was assessed by measuring cell viability after drug exposure. Results: A framework for rapid pharmacotyping of PDOs was established across a multi-institutional consortium of academic medical centers. Specimens obtained remotely and shipped to a central biorepository maintain viability and allowed generation of PDOs with 77% success. Early cultures maintain the clonal heterogeneity seen in PDAC with similar phenotypes (cystic-solid). Late cultures exhibit a dominant clone with a pharmacotyping profile similar to early passages. The biomass required for accurate pharmacotyping can be minimized by leveraging a high-throughput technology. Twenty-nine cultures were pharmacotyped to derive a population distribution of chemotherapeutic sensitivity at our center. Pharmacotyping rapidly-expanded PDOs was completed in a median of 48 (range 18-102) days. Conclusions: Rapid development of PDOs from patients undergoing surgery for PDAC is eminently feasible within the perioperative recovery period, enabling the potential for pharmacotyping to guide postoperative adjuvant chemotherapeutic selection. Studies validating PDOs as a promising predictive biomarker are ongoing.
  • Reponen, Elina; Tuominen, Hanna; Korja, Miikka (2019)
    BACKGROUND: Multiple nationwide outcome registries are utilized for quality benchmarking between institutions and individual surgeons. OBJECTIVE: To evaluate whether nationwide quality of care programs in the United Kingdom and United States can measure differences in neurosurgical quality. METHODS: This prospective observational study comprised 418 consecutive adult patients undergoing elective craniotomy at Helsinki University Hospital between December 7, 2011 and December 31, 2012.We recorded outcome event rates and categorized them according to British Neurosurgical National Audit Programme (NNAP), American National Surgical Quality Improvement Program (NSQIP), and American National Neurosurgery Quality and Outcomes Database (N(2)QOD) to assess the applicability of these programs for quality benchmarking and estimated sample sizes required for reliable quality comparisons. RESULTS: The rate of in-hospital major and minor morbidity was 18.7% and 38.0%, respectively, and 30-d mortality rate was 2.4%. The NSQIP criteria identified 96.2% of major but only 38.4% of minor complications. N(2)QOD performed better, but almost one-fourth (23.2%) of all patients with adverse outcomes, mostly minor, went unnoticed. For NNAP, a sample size of over 4200 patients per surgeon is required to detect a 50.0% increase in mortality rates between surgeons. The sample size required for reliable comparisons between the rates of complications exceeds 600 patients per center per year. CONCLUSION: The implemented benchmarking programs in the United Kingdom and United States fail to identify a considerable number of complications in a high-volume center. Health care policy makers should be cautious as outcome comparisons between most centers and individual surgeons are questionable if based on the programs.
  • Kiviniemi, Vesa; Korhonen, Vesa; Kortelainen, Jukka; Rytky, Seppo; Keinanen, Tuija; Tuovinen, Timo; Isokangas, Matti; Sonkajarvi, Eila; Siniluoto, Topi; Nikkinen, Juha; Alahuhta, Seppo; Tervonen, Osmo; Turpeenniemi-Hujanen, Taina; Myllyla, Teemu; Kuittinen, Outi; Voipio, Juha (2017)
    Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography ( DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 mu V followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for bloodbrain barrier disruption augmented drug delivery.
  • Beilmann-Lehtonen, Ines; Böckelman, Camilla; Mustonen, Harri K; Hagström, Jaana; Koskensalo, Selja; Haglund, Caj (2020)
    Colorectal cancer (CRC), the second most common cancer globally, resulted in 881,000 deaths in 2018. Toll-like receptors (TLRs) are crucial to detecting pathogen invasion and inducing the host's immune response. This study aimed to explore the prognostic value of TLR2 and TLR4 tumor expressions in colorectal cancer patients. We studied the immunohistochemical expressions of TLR2 and TLR4 using tissue microarray specimens from 825 patients undergoing surgery in the Department of Surgery, Helsinki University Hospital, between 1982 and 2002. We assessed the relationships between TLR2 and TLR4 expressions and clinicopathological variables and patient survival. We generated survival curves using the Kaplan-Meier method, determining significance with the log-rank test. Among patients with lymph node-positive disease and no distant metastases (Dukes C), a strong TLR2 immunoactivity associated with a better prognosis (p <0.001). Among patients with local Dukes B disease, a strong TLR4 immunoactivity associated with a worse disease-specific survival (DSS; p = 0.017). In the multivariate survival analysis, moderate TLR4 immunoactivity compared with strong TLR4 immunoactivity (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.49-0.89, p = 0.007) served as an independent prognostic factor. In the multivariate analysis for the Dukes subgroups, moderate TLR2 immunoactivity (HR 2.63, 95% CI 1.56-4.44, p <0.001) compared with strong TLR2 immunoactivity served as an independent negative prognostic factor in the Dukes C subgroup. TLR2 and TLR4 might be new prognostic factors to indicate which CRC patients require adjuvant therapy and which could spare from an unnecessary follow-up, but further investigations are needed.
  • Hasnat, Shrabon; Hujanen, Roosa; Nwaru, Bright I.; Salo, Tuula; Salem, Abdelhakim (2020)
    Head and neck squamous cell carcinoma (HNSCC) is a group of tumours which exhibit low 5 year survival rates. Thus, there is an urgent need to identify biomarkers that may improve the clinical utility of patients with HNSCC. Emerging studies support a role of toll-like receptors (TLRs) in carcinogenesis. Therefore, this systematic review and meta-analysis was performed to assess the prognostic value of TLR immunoexpression in HNSCC patients. We compiled the results of thirteen studies comprising 1825 patients, of which six studies were deemed qualified for quantitative synthesis. The higher immunoexpression of TLR-1 to 5 and 9 was associated with a worsening of the clinical parameters of patients with HNSCC. Furthermore, induced levels of TLR-3, 4, 5, 7 and 9 were found to predict the patients' survival time. The meta-analysis revealed that TLR-7 overexpression is associated with a decreased mortality risk in HNSCC patients (HR 0.51; 95%CI 0.13-0.89; I2 34.6%), while a higher expression of TLR-5 predicted shorter, but non-significant, survival outcome. In conclusion, this review suggests that TLRs may represent some prognostic value for patients with HNSCC. However, due to small sample sizes and other inherent methodological limitations, more well designed studies across different populations are still needed before TLRs can be recommended as a reliable clinical risk-stratification tool.
  • Martins, João Pedro; das Neves, José; de la Fuente, María; Celia, Christian; Florindo, Helena; Günday-Türeli, Nazende; Popat, Amirali; Luis Santos, José; Sousa, Flávia; Schmid, Ruth; Wolfram, Joy; Sarmento, Bruno; Santos, Hélder A. (2020)
    This commentary article conveys the views of the board of the Nanomedicine and Nanoscale Delivery Focus Group of the Controlled Release Society regarding the decision of the United States National Cancer Institute (NCI) in halting funding for the Centers of Cancer Nanotechnology Excellence (CCNEs), and the subsequent editorial articles that broadened this discussion.
  • Peltonen, Karita; Feola, Sara; Umer, Husen M.; Chiaro, Jacopo; Mermelekas, Georgios; Ylösmaki, Erkko; Pesonen, Sari; Branca, Rui M. M.; Lehtiö, Janne; Cerullo, Vincenzo (2021)
    Simple Summary Immunotherapy has revolutionized cancer treatment, yet many tumors remain resistant to current immuno-oncology therapies. Here we explore a novel, customized oncolytic adenovirus vaccine platform as immunotherapy in a resistant tumor model. We present a workflow for customizing the oncolytic vaccine for improved tumor targeting. This targeting is based on experimentally discovered tumor antigens, which are incorporated as active components of the vaccine formulation. The pipeline may be further applied for designing personalized therapeutic cancer vaccines. Knowledge of clinically targetable tumor antigens is becoming vital for broader design and utility of therapeutic cancer vaccines. This information is obtained reliably by directly interrogating the MHC-I presented peptide ligands, the immunopeptidome, with state-of-the-art mass spectrometry. Our manuscript describes direct identification of novel tumor antigens for an aggressive triple-negative breast cancer model. Immunopeptidome profiling revealed 2481 unique antigens, among them a novel ERV antigen originating from an endogenous retrovirus element. The clinical benefit and tumor control potential of the identified tumor antigens and ERV antigen were studied in a preclinical model using two vaccine platforms and therapeutic settings. Prominent control of established tumors was achieved using an oncolytic adenovirus platform designed for flexible and specific tumor targeting, namely PeptiCRAd. Our study presents a pipeline integrating immunopeptidome analysis-driven antigen discovery with a therapeutic cancer vaccine platform for improved personalized oncolytic immunotherapy.
  • Cervera-Carrascon, V.; Siurala, M.; Santos, J. M.; Havunen, R.; Tähtinen, S.; Karell, P.; Sorsa, S.; Kanerva, A.; Hemminki, A. (2018)
    Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p <0.0001) and overall survival (p <0.01) were improved. In this set-up, the addition of adoptive cell therapy with OT-I lymphocytes did not increase efficacy further. When virus injections were initiated before antibody treatment in a prime-boost approach, 100% of tumors regressed completely and all mice survived. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells. These preclinical studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) is used in melanoma patients receiving an anti-PD-1 antibody.