Tumor Biology - Volume 43, issue 1

Authors: Biesaga, Beata | Kołodziej–Rzepa, M. | Janecka–Widła, A. | Słonina, D. | Halaszka, K. | Przewoźnik, M. | Mucha-Małecka, A.

Article Type: Research Article

Abstract: BACKGROUND: HPV-16 positivity in patients with squamous cell carcinoma of oropharynx (OPSCC) is associated with better prognosis. However, in more than 40% of HPV infected patients progression of cancer disease is observed, which indicates the presence of cancer cells resistant to therapy. Some studies suggest that there may be a subpopulation of cancer stem cells (CSCs), which simultaneously exhibit unlimited ability to self-renew and differentiate towards neoplastic cells. The relation between HPV16 infection and biomarkers of CSCs is unclear. OBJECTIVE: The aim of the study was to compare the expression of CD44, CD98, ALDH1/2 and P16 in oropharyngeal …cancer patients with or without HPV16 infection, as well as to analyze the prognostic potential of selected CSCs biomarkers in these two subgroups. METHODS: The study was performed in a group of 63 patients. HPV16 infection status was analyzed by quantitative polymerase chain reaction, while CD44, CD98, ALDH1/2 and P16 expression by immunohistochemistry. In survival analysis, two endpoints were applied: overall survival (OS) and disease-free survival (DFS). RESULTS: Among 63 cancers, HPV16 infection was found in 25 tumors (39.7%), overexpression of CD44, CD98, ALDH1/2 and P16 in 43 (68.2%), 30 (47.6%), 33 (52.4%) and 27 (42.9%) cancers, respectively. In the HPV16-positive subgroup, DFS rate of 100% was observed in patients with tumors characterized by lack of CD44 overexpression and those treated with concurrent chemoradiotherapy with cisplatin (CisPt-CRT). In the HPV16-negative subgroup 100% of DFS was noticed for patients (n  = 6) with P16 immunopositive tumors. In this subgroup none of the CSCs biomarkers evaluated in the study had any impact on OS or DFS. In patients with HPV16-positive oropharyngeal cancer, lack of CD44 overexpression and application of CisPt-CRT were found to be positive prognostic factors. Show more

Keywords: Oropharynx, cancers, HPV16, cancer stem cells, biomarkers, prognosis

DOI: 10.3233/TUB-200049

Citation: Tumor Biology, vol. 43, no. 1, pp. 99-113, 2021

Authors: Muller, Mirte | Hoogendoorn, Roland | Moritz, Ruben J.G. | van der Noort, Vincent | Lanfermeijer, Mirthe | Korse, Catharina M. | van den Broek, Daan | ten Hoeve, Jelle J. | Baas, Paul | van Rossum, Huub H. | van den Heuvel, Michel M.

Article Type: Research Article

Abstract: BACKGROUND: The widespread introduction of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) has led to durable responses but still many patients fail and are treated beyond progression. OBJECTIVE: This study investigated whether readily available blood-based tumor biomarkers allow accurate detection of early non-responsiveness, allowing a timely switch of therapy and cost reduction. METHODS: In a prospective, observational study in patients with NSCLC treated with nivolumab or pembrolizumab, five serum tumor markers were measured at baseline and every other week. Six months disease control as determined by RECIST was used as a measure of …clinical response. Patients with a disease control <  6 months were deemed non-responsive. For every separate tumor marker a criterion for predicting of non-response was developed. Each marker test was defined as positive (predictive of non-response) if the value of that tumor marker increased at least 50% from the value at baseline and above a marker dependent minimum value to be determined. Also, tests based on combination of multiple markers were designed. Specificity and sensitivity for predicting non-response was calculated and results were validated in an independent cohort. The target specificity of the test for detecting non-response was set at >  95%, in order to allow its safe use for treatment decisions. RESULTS: A total of 376 patients (training cohort: 180, validation cohort: 196) were included in our analysis. Results for the specificity of the single marker tests in the validation set were CEA: 98·3% (95% CI: 90·9–100%), NSE: 96·5% (95% CI: 87·9–99·6%), SCC: 96·5% (95% CI: 88·1–99·6%), Cyfra21·1 : 91.8% (95% CI: 81·9–97·3%), and CA125 : 86·0% (95% CI: 74·2–93·7%). A test based on the combination of Cyfra21.1, CEA and NSE accurately predicted non-response in 32.3% (95% CI 22.6–43.1%) of patients 6 weeks after start of immunotherapy. Survival analysis showed a significant difference between predicted responders (Median PFS: 237 days (95% CI 184–289 days)) and non-responders (Median PFS: 58 days (95% CI 46–70 days)) (p  <  0.001). CONCLUSIONS: Serum tumor marker based tests can be used for accurate detection of non-response in NSCLC, thereby allowing early and safe discontinuation of immunotherapy in a significant subset of patients. Show more

Keywords: Serum tumor marker, CEA, Cyfra, SCC, NSE, CA125, Nivolumab, response, Longitudinal

DOI: 10.3233/TUB-211504

Citation: Tumor Biology, vol. 43, no. 1, pp. 115-127, 2021

Authors: Brito, Angelo Borsarelli Carvalho | Delamain, Marcia Torresan | Fanelli, Marcello Ferreti | Soares, Fernando Augusto | de Souza, Cármino Antônio | Vassallo, José | Lima, Carmen Silvia Passos

Article Type: Research Article

Abstract: OBJECTIVES: Single nucleotide variants (SNVs) in vascular endothelial growth factor A (VEGFA ) and VEGFA receptor (KDR ) genes confer different inherited abilities in angiogenesis (AG) pathway. We aimed in the present study to evaluate influence of six VEGFA and four KDR SNVs in clinical features and survival of diffuse large B-cell lymphoma (DLBCL) patients. METHODS: One hundred and sixty-eight DLBCL patients diagnosed between June 2009-September 2014 were enrolled in the study. Patients were homogeneously treated with R-CHOP. Genotypes were identified in genomic DNA by real-time polymerase chain reaction. RESULTS: Patients with VEGFA …-634CC and +936CT or TT genotypes were at increased risk of showing grade III / IV toxicities and not achieving complete remission with treatment, and shorter event-free and overall survival were seen in patients with VEGFA -1154GA or AA genotype and VEGFA ATAGCC haplotype. CONCLUSION: Our data suggest that inherited abnormalities in AG’s gene modulate clinical features and prognosis of DLBCL patients homogeneously treated with R-CHOP. Show more

Keywords: Diffuse large B-cell lymphoma, angiogenesis, genetic variants, prognosis

DOI: 10.3233/TUB-211510

Citation: Tumor Biology, vol. 43, no. 1, pp. 129-140, 2021

Authors: Zarin, Bahare | Rafiee, Laleh | Daneshpajouhnejad, Parnaz | Haghjooy Javanmard, Shaghayegh

Article Type: Review Article

Abstract: Cancers evolve as a result of the accelerated proliferation of cancer cells in a complicated, enriched, and active microenvironment. Tumor microenvironment (TME) components are the master regulators of any step of cancer development. The tumor microenvironment is composed of many cellular and noncellular components that contribute to the evolution of cancer cells. Cancer-associated fibroblasts (CAFs) are activated fibroblasts in the TME that implicate in tumor progression and metastasis dissemination through secretion of oncogenic factors which are carried to the secondary metastatic sites through exosomes. In this review, we aimed to assess the role of CAF-derived exosomes in TME construction and …pre-metastatic niche formation in different cancers of the digestive system in order to better understand some important mechanisms of metastasis and provide possible targets for clinical intervention. This review article is divided into two thematic parts explaining the general mechanisms of pre-metastatic niche formation and metastasis and the role of CAF-derived exosomes in different digestive system cancers including colorectal, gastric, esophageal, pancreatic, and liver cancers. Show more

Keywords: Gastrointestinal cancers, tumor microenvironment, metastasis, CAFs, CAF-derived exosomes

DOI: 10.3233/TUB-200075

Citation: Tumor Biology, vol. 43, no. 1, pp. 141-157, 2021

Authors: Epstein, Richard J.

Article Type: Review Article

Abstract: The human TMPRSS2 gene is pathogenetically implicated in both coronaviral lung infection and prostate cancer, suggesting its potential as a drug target in both contexts. SARS-COV-2 spike polypeptides are primed by the host transmembrane TMPRSS2 protease, triggering virus fusion with epithelial cell membranes followed by an endocytotic internalisation process that bypasses normal endosomal activation of cathepsin-mediated innate immunity; viral co-opting of TMPRSS2 thus favors microbial survivability by attenuating host inflammatory responses. In contrast, most early hormone-dependent prostate cancers express TMPRSS2:ERG fusion genes arising from deletions that eliminate the TMPRSS2 coding region while juxtaposing its androgen-inducible promoter and …the open reading frame of ERG , upregulating pro-inflammatory ERG while functionally disabling TMPRSS2 . Moreover, inflammatory oxidative DNA damage selects for TMPRSS2:ERG -fused cancers, whereas patients treated with antiinflammatory drugs develop fewer of these fusion-dependent tumors. These findings imply that TMPRSS2 protects the prostate by enabling endosomal bypass of pathogens which could otherwise trigger inflammation-induced DNA damage that predisposes to TMPRSS2:ERG fusions. Hence, the high oncogenic selectability of TMPRSS2:ERG fusions may reflect a unique pro-inflammatory synergy between androgenic ERG gain-of-function and fusogenic TMPRSS2 loss-of-function, cautioning against the use of TMPRSS2-inhibitory drugs to prevent or treat early prostate cancer. Show more

Keywords: Prostate cancer, host defense, proteases, inflammation, innate immunity, SARS-COV-2, COVID-19

DOI: 10.3233/TUB-211502

Citation: Tumor Biology, vol. 43, no. 1, pp. 159-176, 2021

Authors: Al-Zaidan, Lobna | Mestiri, Sarra | Raza, Afsheen | Merhi, Maysaloun | Inchakalody, Varghese Philipose | Fernandes, Queenie | Taib, Nassiba | Uddin, Shahab | Dermime, Said

Article Type: Review Article

Abstract: Pneumonia cases of unknown etiology in Wuhan, Hubei province, China were reported to the World Health Organization on 31st of December 2019. Later the pathogen was reported to be a novel coronavirus designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Corona virus disease 2019 (COVID-19). The disease outspread was followed by WHO declaration of COVID-19 pandemic as a “Public Health Emergency of International Concern”. SARS-CoV-2 is a novel pathogenic beta coronavirus that infects humans causing severe respiratory illness. However, multifarious factors can contribute to the susceptibility to COVID-19 related morbidity and mortality such as age, gender, and …underlying comorbidities. Infection initiates when viral particles bind to the host cell surface receptors where SARS-CoV-2 spike glycoprotein subunit 1 binds to the Angiotensin Converting Enzyme 2 (ACE2). It is of importance to mention that SARS-CoV and SARS-CoV-2 viruses’ mediate entry into the host cells via ACE2 receptor which might be correlated with the structural similarity of spike glycoprotein subunit 1 of both SARS viruses. However, the structural binding differs, whereas ACE2 receptor binding affinity with SARS-CoV-2 is 4 folds higher than that with SARS-CoV. Moreover, amino acids sequence divergence between the two S glycoproteins might be responsible for differential modulations of the specific immune response to both viruses. Identification of different aspects such as binding affinity, differential antigenic profiles of S-glycoproteins, and ACE2 mutations might influence the investigation of potential therapeutic strategies targeting SARS-CoV-2/ACE2 binding interface. In this review, we aim to elaborate on the expression of hACE2 receptor protein and its binding with SARS-CoV-2 S1 subunit, the possible immunogenic sequences of spike protein, effect of ACE 2 polymorphism on viral binding, and infectivity/susceptibility to disease. Furthermore, targeting of hACE2 receptor binding with SARS-CoV-2 S1 subunit via various mechanisms will be discussed to understand its role in therapeutics. Show more

Keywords: COVID-19, SARS-CoV-2, ACE2 receptor, spike glycoprotein, ACE2 polymorphism, S glycoprotein immunogenic sequences

DOI: 10.3233/TUB-200084

Citation: Tumor Biology, vol. 43, no. 1, pp. 177-196, 2021

Authors: Do Carmo Silva, Joana | Vesely, Stepan | Luksanova, Hana | Prusa, Richard | Babjuk, Marko

Article Type: Research Article

Abstract: BACKGROUND: The role of isoforms of prostate specific antigen (PSA) and other kallikrein-related markers in early detection of biochemical recurrence (BCR) after radical prostatectomy (RP) is not well known and serum PSA is currently used in preoperative risk nomograms. OBJECTIVE: The aim of this research was to study pre- and early postoperative levels of important PSA isoforms and human kallikrein-2 to determine their ability to predict BCR and identify disease persistence (DP). METHODS: This study included 128 consecutive patients who underwent RP for clinically localized prostate cancer. PSA, fPSA, %fPSA, [–2]proPSA, PHI and hK2 were measured …preoperatively, at 1 and 3 months after RP. We determined the ability of these markers to predict BCR and identify DP. RESULTS: The DP and BCR rate were 11.7%and 20.3%respectively and the median follow up was 64 months (range 3–76 months). Preoperatively, the independent predictors of BCR were PSA (p -value 0.029), [–2]proPSA (p -value 0.002) and PHI (p -value 0.0003). Post-RP, PSA was the single marker correlating with BCR, both at one (p -value 0.0047) and 3 months (p -value 0.0004). PSA, fPSA, [–2]proPSA and PHI significantly correlated to DP at 1 and 3 months post-RP (p -value <  0.05), although PSA had the most significant existing correlation (p -value <  0.0001). CONCLUSIONS: [–2]proPSA and PHI are preoperative predictors of BCR and DP that outperform the currently used serum PSA. At the early postoperative period there is no additional benefit of the other markers tested. Show more

Keywords: Prostate cancer, biochemical recurrence, prostate health index, (–2) pro-prostate specific antigen, PSA isoforms

DOI: 10.3233/TUB-211509

Citation: Tumor Biology, vol. 43, no. 1, pp. 197-207, 2021

Authors: Ali, Haytham | Olsson, Lina | Lindmark, Gudrun | Hammarström, Marie-Louise | Hammarström, Sten | Sitohy, Basel

Article Type: Research Article

Abstract: OBJECTIVE: The microenvironment of colon cancer (CC) is heterogeneous including cells of myeloid lineage affecting tumor growth and metastasis. Two functional subtypes of myeloid cells have been identified; one (M1) is tumor-inhibitory and the other one (M2) is tumor-promoting. Whether the three myeloid markers EMR1, CD206 and CD86 are expressed only in the infiltrating myeloid cells or also in the tumor cells was investigated. METHODS: Expression of the myeloid markers was investigated in CC at the mRNA and protein levels in primary tumors and lymph nodes. mRNA expression was also determined in 5 CC cell lines. Protein expression …was investigated by two-color immunofluorescence and consecutive-sections-immune-staining combined with morphometry using specific antibodies for the myeloid cell markers and the epithelial cell markers CEACAM5 and EpCAM. RESULTS: EMR1 and CD86, but not CD206, mRNA levels were significantly higher in CC primary tumors compared to apparently normal colon tissue (P  <  0.0001). EMR1 mRNA levels were significantly higher in both hematoxylin-eosin positive (H&E(+)) and H&E(–) lymph nodes of CC patients compared to control nodes (P  = 0.03 and P  = 0.01, respectively). EMR1 and CD206 mRNAs were expressed in 4/5 and 5/5 CC cell lines, respectively, while CD86 mRNA was not expressed. Immuno-morphometry revealed that about 20% of the tumor cells expressed EMR1 and CD206. Positive cells were tumor cells as revealed by anti-CEACAM5 and anti-EpCAM staining. The number of EMR1, CD206 and CD86 positive cells were significantly increased in CC primary tumors compared to normal colon tissue (P  <  0.0001). However, CD206 was also expressed in normal colonocytes. Only EMR1 showed significantly increased numbers of positive tumor cells in H&E(+) nodes compared to H&E(-) nodes (P  = 0.001). EMR1 expression in CC tumor cells correlated with CXCL17 expressing tumor cells. CONCLUSION: EMR1, like the chemokine CXCL17, is ectopically expressed in colon cancer possibly in the same cancer cells. Show more

Keywords: EMR1, CD206, CD86, chemokines, epithelial cell markers

DOI: 10.3233/TUB-200082

Citation: Tumor Biology, vol. 43, no. 1, pp. 209-223, 2021

Authors: Askar, Mostafa A. | El Shawi, Omama E. | Abou zaid, Omayma A.R. | Mansour, Nahla A. | Hanafy, Amal M.

Article Type: Research Article

Abstract: BACKGROUND: The limitations of surgery, radiotherapy, and chemotherapy in cancer treatment and the increase in the application of nanomaterials in the field of biomedicine have promoted the use of nanomaterials in combination with radiotherapy for cancer treatment. OBJECTIVE: To improve the efficiency of cancer treatment, curcumin-naringenin loaded dextran-coated magnetic nanoparticles (CUR-NAR-D-MNPs) were used as chemotherapy and in combination with radiotherapy to verify their effectiveness in treating tumors. METHODS: CUR-NAR-D-MNPs were prepared and studied by several characterization methods. Median inhibitory concentration (IC50) and cellular toxicity were evaluated by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell death and radiosensitization …were studied by acridine orange/ethidium bromide dual staining of MCF-7 human breast cancer cells. RESULTS: CUR-NAR-D-MNPs induce apoptosis and inhibited cell proliferation through reactive oxygen species (ROS) generation. CUR-NAR-D-MNPs used alone had a certain therapeutic effect on tumors. CUR-NAR-D-MNPs plus radiotherapy significantly reduced the tumor volume and led to cell cycle arrest and induction of apoptosis through modulation of P53high , P21high , TNF-αlow , CD44low , and ROShigh signaling CONCLUSIONS: CUR-NAR-D-MNPs are effective in the treatment of tumors when combined with radiotherapy, and show radiosensitization effects against cancer proliferation in vitro and in vivo . Show more

Keywords: Curcumin-narenginin, magnetite-nanoparticles, radiosensitization, antitumor, in-vitro , in-vivo studies

DOI: 10.3233/TUB-211506

Citation: Tumor Biology, vol. 43, no. 1, pp. 225-247, 2021

Authors: Jauhiainen, Maria K. | Xu, Man | Pyöriä, Lari | Atula, Timo | Aro, Katri | Markkanen, Anttoni | Haglund, Caj | Hagström, Jaana | Mäkitie, Antti A. | Söderlund-Venermo, Maria | Sinkkonen, Saku T.

Article Type: Research Article

Abstract: BACKGROUND: The etiology of salivary gland tumors is mainly unknown. The anatomical location of the salivary glands, with the mucosal pathway to the oral cavity and its rich microbiome, raises the question of potential viral background. OBJECTIVE: This study focuses on the potential presence of herpes-, polyoma- and parvoviruses in pleomorphic adenoma (PA), recurrent pleomorphic adenoma (RPA) and carcinoma ex pleomorphic adenoma (CaxPA). METHODS: Thirty different viruses were analyzed by PCR-based assays in 68 formalin-fixed paraffin-embedded salivary gland tumors (25 PA, 31 RPA and 12 CaxPA). RESULTS: Virus DNA was detected altogether in 19/68 …(28%) tumor samples. Human herpesviruses 6B and 7 (HHV-6B and HHV-7) and Epstein-Barr virus (EBV) were frequently and almost exclusively found in CaxPA (5/12, 7/12, and 3/12, respectively). Within the 7 CaxPA that were virus-positive, 3 samples contained 3, and 1 sample even 4, different viruses. Infrequent viral positivity was shown for parvovirus B19 and cutavirus, as well as Merkel cell and Malawi polyomaviruses. CONCLUSIONS: Our unexpected finding of herpesvirus DNA almost exclusively in CaxPA tissues deserves further in-depth studies. Show more

Keywords: Pleomorphic adenoma, recurrent pleomorphic adenoma, carcinoma ex pleomorphic adenoma, viral etiology, herpesvirus

DOI: 10.3233/TUB-211519

Citation: Tumor Biology, vol. 43, no. 1, pp. 249-259, 2021