Tumor Biology - Volume 43, issue 1

Authors: Söder, Birgitta | Källmén, Håkan | Yucel-Lindberg, Tülay | Meurman, Jukka H.

Article Type: Research Article

Abstract: BACKGROUND: Oral infections associate statistically with cancer. OBJECTIVE: We hypothesized that certain periodontal microorganisms might specifically link to malignancies in general and set out to investigate this in our ongoing cohort study. METHODS: A sample of 99 clinically examined patients from our cohort of 1676 subjects was used to statistically investigate the associations between harboring periodontal microorganisms Aggregatibacter actinomycetemcomitans (A.a ), Porphyromonas gingivalis (P.g ), Prevotella intermedia (P.i ), Tannerella forsythia (T.f ) and Treponema denticola (T.d ). We used oral infection indexes and the incidence figures of malignancies as registered …in 2008–2016 in the Swedish National Cancer Register. RESULTS: The pathogen A.a showed strong association with malignancy in 32 out of the 99 patients while P.g and P.i were more prevalent among patients without malignancy. In principal component analyses, A.a appeared in the strongest component while the second strongest component consisted of a combination of T.f and T.d . The third component consisted of a combination of P.g and P.i, respectively. Of basic and oral health variables, gingival index appeared to be the strongest expression of inflammation (Eigen value 4.11 and Explained Variance 68.44 percent). CONCLUSIONS: The results partly confirmed our hypothesis by showing that harboring certain periodontal bacteria might link to malignancy. However, the associations are statistical and no conclusions can be drawn about causality. Show more

Keywords: Bacteria, cancer, epidemiology, malignant disease, periodontitis

DOI: 10.3233/TUB-200066

Citation: Tumor Biology, vol. 43, no. 1, pp. 1-9, 2021

Authors: Busch, Maike | Miroschnikov, Natalia | Dankert, Jaroslaw Thomas | Wiesehöfer, Marc | Metz, Klaus | Stephan, Harald | Dünker, Nicole

Article Type: Research Article

Abstract: BACKGROUND: Retinoblastoma (RB) is the most common childhood eye cancer. Chemotherapeutic drugs such as etoposide used in RB treatment often cause massive side effects and acquired drug resistances. Dysregulated genes and miRNAs have a large impact on cancer progression and development of chemotherapy resistances. OBJECTIVE: This study was designed to investigate the involvement of retinoic acid receptor alpha (RAR α) in RB progression and chemoresistance as well as the impact of miR-138, a potential RAR α regulating miRNA. METHODS: RAR α and miR-138 expression in etoposide resistant RB cell lines and chemotherapy treated patient tumors compared …to non-treated tumors was revealed by Real-Time PCR. Overexpression approaches were performed to analyze the effects of RAR α on RB cell viability, apoptosis, proliferation and tumorigenesis. Besides, we addressed the effect of miR-138 overexpression on RB cell chemotherapy resistance. RESULTS: A binding between miR-138 and RAR α was shown by dual luciferase reporter gene assay. The study presented revealed that RAR α is downregulated in etoposide resistant RB cells, while miR-138 is endogenously upregulated. Opposing RAR α and miR-138 expression levels were detectable in chemotherapy pre-treated compared to non-treated RB tumor specimen. Overexpression of RARα increases apoptosis levels and reduces tumor cell growth of aggressive etoposide resistant RB cells in vitro and in vivo. Overexpression of miR-138 in chemo-sensitive RB cell lines partly enhances cell viability after etoposide treatment. CONCLUSIONS: Our findings show that RAR α acts as a tumor suppressor in retinoblastoma and is downregulated upon etoposide resistance in RB cells. Thus, RAR α may contribute to the development and progression of RB chemo-resistance. Show more

Keywords: Retinoblastoma, RB, RARα, miR-138, chemotherapy, chemoresistance, drug resistance, etoposide, CAM assay

DOI: 10.3233/TUB-200072

Citation: Tumor Biology, vol. 43, no. 1, pp. 11-26, 2021

Authors: Apu, Mohd Nazmul Hasan | Aktar, Most. Nasrin | Rahman, Md Morshadur | Mostaid, Md Shaki

Article Type: Research Article

Abstract: OBJECTIVES: Genetic susceptibility to cervical cancer in relation to transforming growth factor beta 1 (TGFB1 ) gene polymorphisms has not been investigated extensively among the women in Bangladesh. So, the aim of this study was to find out the correlation of the polymorphisms of TGFB1 C509T (rs1800469) and T869C (rs1800470) with the risk of cervical cancer among the Bangladeshi women. STUDY DESIGN: 134 cervical cancer patients and 102 age-sex matched healthy controls were included from two institutions in Bangladesh. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for genotyping two TGFB1 single nucleotide polymorphisms …C509T (rs1800469) and T869C (rs1800470) in patients and controls. RESULTS: No significant correlation was found between polymorphisms C509T (rs1800469) and T869C (rs1800470) of TGFB1 gene with cervical cancer in Bangladeshi women. In case of the cervical cancer patients who had first degree relatives with cancer were prone to carry the polymorphic version of the TGFB1 gene polymorphism at C509T (OR = 5.597, 95% CI = 1.224–25.597, p  < 0.05 ) but may not result in the increase of developing cervical cancer. CONCLUSION: In summary, two polymorphisms C509T and T869C of TGFB1 gene may not be associated with cervical cancer risk in Bangladeshi women. Show more

Keywords: TGFB1 gene polymorphisms, C509T, T869C, Cervical cancer, Bangladesh

DOI: 10.3233/TUB-200061

Citation: Tumor Biology, vol. 43, no. 1, pp. 27-35, 2021

Authors: Gavamukulya, Yahaya | Maina, Esther N. | El-Shemy, Hany A. | Meroka, Amos M. | Kangogo, Geoffrey K. | Magoma, Gabriel | Wamunyokoli, Fred

Article Type: Research Article

Abstract: BACKGROUND: Green synthesized nanoparticles have been earmarked for use in nanomedicine including for the development of better anticancer drugs. OBJECTIVE: The aim of this study was to undertake biochemical evaluation of anticancer activities of green synthesized silver nanoparticles (AgNPs) from ethanolic extracts of fruits (AgNPs-F) and leaves (AgNPs-L) of Annona muricata . METHODS: Previously synthesized silver nanoparticles were used for the study. The effects of the AgNPs and 5-Fluorouracil were studied on PC3, HeLa and PNT1A cells. The resazurin, migration and colonogenic assays as well as qRT-PCR were employed. RESULTS: The AgNPs-F displayed significant …antiproliferative effects against HeLa cells with an IC50 of 38.58μ g/ml and PC3 cells with an IC50 of 48.17μ g/ml but selectively spared normal PNT1A cells (selectivity index of 7.8), in comparison with first line drug 5FU and AgNPs-L whose selectivity index were 3.56 and 2.26 respectively. The migration assay revealed potential inhibition of the metastatic activity of the cells by the AgNPs-F while the colonogenic assay indicated the permanent effect of the AgNPs-F on the cancer cells yet being reversible on the normal cells in contrast with 5FU and AgNPs-L. CASP9 was significantly over expressed in all HeLa cells treated with the AgNPs-F (1.53-fold), AgNPs-L (1.52-fold) and 5FU (4.30-fold). CXCL1 was under expressed in HeLa cells treated with AgNPs-F (0.69-fold) and AgNPs-L (0.58-fold) and over expressed in cells treated with 5FU (4.95-fold), but the difference was not statistically significant. CXCR2 was significantly over expressed in HeLa cells treated with 5FU (8.66-fold) and AgNPs-F (1.12-fold) but under expressed in cells treated with AgNPs-L (0.76-fold). CONCLUSIONS: Here we show that biosynthesized AgNPs especially AgNPs-F can be used in the development of novel and better anticancer drugs. The mechanism of action of the AgNPs involves activation of the intrinsic apoptosis pathway through upregulation of CASP9 and concerted down regulation of the CXCL1/ CXCR2 gene axis. Show more

Keywords: Silver nanoparticles, HeLa, PC3, PNT1A, CASP9 , CXCL1/CXCR2

DOI: 10.3233/TUB-200058

Citation: Tumor Biology, vol. 43, no. 1, pp. 37-55, 2021

Authors: Björkman, Kajsa | Mustonen, Harri | Kaprio, Tuomas | Kekki, Henna | Pettersson, Kim | Haglund, Caj | Böckelman, Camilla

Article Type: Research Article

Abstract: OBJECTIVES: The tumor stage represents the single most important prognostic factor for colorectal cancer (CRC), although more accurate prognostics remain much needed. Previously, we identified CA125 as an independent significant prognostic factor, which we have further validated along with CEA, CA19-9, and CA242 in a large cohort of CRC patients. METHODS: Using enzyme-linked immunosorbent assays, we analyzed preoperative serum samples in 322 CRC patients operated on between 1998 and 2003. RESULTS: Using the Spearman’s rho model, we calculated the correlation between our previous findings on MUC16 and CA125, for which the correlation coefficient was 0.808 (p … < 0.001). The Cox regression analysis of the linear and logarithmic values of CEA, CA125, CA242, and CA19-9 identified only CA125 (hazard ratio [HR] 1.03; 95% confidence interval [95% CI] 1.02−1.04; p  < 0.001) as significant when using the linear values. Survival among CRC patients with a high CA125 level was poor compared with CRC patients with a low CA125 level (HR 2.48; 95% CI 1.68–3.65; p  < 0.001). In subgroup analyses, patients with high CA125 levels and aged ≤67 or >67, with stage I–II or III–IV, and both colon and rectal cancer exhibited poor prognoses. In the multivariate analysis, we used clinical pathological variables in the model, where age, gender, and stage served as the background characteristics. We dichotomized CA125 using the Youden maximal cutoff point, and the median values for CEA, CA19-9, and CA242. CA125 emerged as the only marker remaining significant and independent together with stage, location, and age (HR 1.91; 95% CI 1.24–2.95; p 0.003). CONCLUSIONS: CA125 represents a significant and independent prognostic factor in CRC patients, superior to CEA. Furthermore, CA242 served as a better prognostic marker than both CEA and CA19-9. We recommend including both CA125 and CA242 in prognostic clinical trials among CRC patients. Show more

Keywords: Colon cancer, rectum cancer, serum samples, cancer prognostics, ELISA

DOI: 10.3233/TUB-200069

Citation: Tumor Biology, vol. 43, no. 1, pp. 57-70, 2021

Article Type: Correction

DOI: 10.3233/TUB-219001

Citation: Tumor Biology, vol. 43, no. 1, pp. 71-71, 2021

Article Type: Correction

DOI: 10.3233/TUB-219002

Citation: Tumor Biology, vol. 43, no. 1, pp. 73-73, 2021

Article Type: Correction

DOI: 10.3233/TUB-219003

Citation: Tumor Biology, vol. 43, no. 1, pp. 75-76, 2021

Authors: Jeethy Ram, T. | Lekshmi, Asha | Somanathan, Thara | Sujathan, K.

Article Type: Review Article

Abstract: Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to …survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention. Show more

Keywords: Epigenetic modification, glycosylation, Galectin-3, carcinogenesis, tumor prevention

DOI: 10.3233/TUB-200051

Citation: Tumor Biology, vol. 43, no. 1, pp. 77-96, 2021

Authors: Nap, Marius | Stieber, Petra

Article Type: Obituary

DOI: 10.3233/TUB-219004

Citation: Tumor Biology, vol. 43, no. 1, pp. 97-98, 2021

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

Article Type: Correction

DOI: 10.3233/TUB-219008

Citation: Tumor Biology, vol. 43, no. 1, pp. 261-262, 2021

Authors: Aguiar, Graziela de Moura | Ramão, Anelisa | Plaça, Jessica Rodrigues | Simões, Sarah Capelupe | Scaraboto, Natália Volgarine | Freitas-Castro, Felipe | Cardoso, Cibele | Sousa, Josane de Freitas | Silva Jr , Wilson Araújo

Article Type: Research Article

Abstract: BACKGROUND: Expression dysregulation of HOX homeobox genes has been observed in several cancers, including head and neck squamous cell carcinoma (HNSC). Although characterization of HOX gene roles in HNSC development has been reported, there is still a need to better understand their real contribution to tumorigenesis. OBJECTIVE: The present study aimed to evaluate the contribution of the protein-coding HOX genes (HOXA10 , HOXC9 , HOXC10 , and HOXC13 ) in cellular processes related to carcinogenesis and progression of the HNSC. METHODS: Expression of HOX genes was analyzed in HNSC RNA-Seq data from …The Cancer Genome Atlas (TCGA) and by RT-qPCR in different tumor cell lines. siRNA-mediated knockdown of HOXA10 , HOXC9 , HOXC10 or HOXC13 was performed in HNSC cell lines, and predicted transcriptional targets HOX genes was analyzed by bioinformatic. RESULTS: Thirty-one out of the 39 mammalian HOX genes were found upregulated in HNSC tissues and cell lines. The HOXC9 , HOXC10 or HOXC13 knockdown attenuated cell migration, and lead to downregulation of epithelial-mesenchymal transition (EMT) markers, which were predicted as transcriptional targets of these three HOX genes. Diminished colony formation and cell cycle arrest after HOXC10 or HOXC13 knockdown were also observed, corroborating the fact that there was an enrichment for genes in proliferation/cell cycle pathways. CONCLUSIONS: In summary, we revealed roles for HOXC9 , HOXC10 , and HOXC13 in cell migration and proliferation/cell cycle progression in HNSC cells and suggested that those HOX members contribute to HNSC development possibly by regulating tumor growth and metastasis. Show more

Keywords: HOX genes, head and neck cancer, bioinformatics, migration, proliferation

DOI: 10.3233/TUB-211525

Citation: Tumor Biology, vol. 43, no. 1, pp. 263-278, 2021

Article Type: Correction

DOI: 10.3233/TUB-219005

Citation: Tumor Biology, vol. 43, no. 1, pp. 279-279, 2021

Article Type: Correction

DOI: 10.3233/TUB-219007

Citation: Tumor Biology, vol. 43, no. 1, pp. 281-281, 2021

Article Type: Addendum

DOI: 10.3233/TUB-219006

Citation: Tumor Biology, vol. 43, no. 1, pp. 283-283, 2021

Authors: Patel, Deep A. | Blay, Jonathan

Article Type: Review Article

Abstract: Peripheral human blood is a readily-accessible source of patient material in which circulating tumour cells (CTCs) can be found. Their isolation and characterization holds the potential to provide prognostic value for various solid cancers. Enumeration of CTCs from blood is becoming a common practice in informing prognosis and may guide therapy decisions. It is further recognized that enumeration alone does not capture perspective on the heterogeneity of tumours and varying functional abilities of the CTCs to interact with the secondary microenvironment. Characterizing the isolated CTCs further, in particular assessing their functional abilities, can track molecular changes in the disease progress. …As a step towards identifying a suite of functional features of CTCs that could aid in clinical decisions, developing a CTC isolation technique based on extracellular matrix (ECM) interactions may provide a more solid foundation for isolating the cells of interest. Techniques based on size, charge, density, and single biomarkers are not sufficient as they underutilize other characteristics of cancer cells. The ability of cancer cells to interact with ECM proteins presents an opportunity to utilize their full character in capturing, and also allows assessment of the features that reveal how cells might behave at secondary sites during metastasis. This article will review some common techniques and recent advances in CTC capture technologies. It will further explore the heterogeneity of the CTC population, challenges they experience in their metastatic journey, and the advantages of utilizing an ECM-based platform for CTC capture. Lastly, we will discuss how tailored ECM approaches may present an optimal platform to capture an influential heterogeneous population of CTCs. Show more

Keywords: CTC, metastasis, EMT, integrins, ECM adhesion

DOI: 10.3233/TUB-210001

Citation: Tumor Biology, vol. 43, no. 1, pp. 285-306, 2021

Article Type: Correction

DOI: 10.3233/TUB-219009

Citation: Tumor Biology, vol. 43, no. 1, pp. 307-307, 2021

Authors: Takeba, Yuko | Ohta, Yuki | Ootaki, Masanori | Kobayashi, Tsukasa | Kida, Keisuke | Watanabe, Minoru | Koizumi, Satoshi | Otsubo, Takehito | Iiri, Taroh | Matsumoto, Naoki

Article Type: Research Article

Abstract: BACKGROUND: Cytokines play an important role in the immune response, angiogenesis, cell growth, and differentiation in hepatocellular carcinoma (HCC). OBJECTIVE: We performed a comprehensive study to identify tumor-related cytokines and pathways involved in HCC pathogenesis. METHODS: Cytokine production was evaluated in human HCC tissues and adjacent non-tumor tissues using an antibody-based protein array technique. We compared cytokine expression in HCC tissues with that of hepatic hemangioma (HH), liver metastasis of colorectal cancer, and noncancerous liver tissues from transplantation donors. The protein levels and localization of the candidate cytokines were analyzed by western blotting and immunohistochemistry. …RESULTS: Increased expression of interleukin (IL)-1 receptor antagonist, macrophage migration inhibitory factor, and IL-16 was observed in HCC and paired adjacent non-tumor tissues compared with noncancerous livers. In addition, there were increased IL-16 levels in HCC tissues compared with HH. IL-16 treatment significantly increased cell proliferation in vitro . The expression of extracellular signal-regulated kinase (ERK)1/2 and cyclin D1 was markedly increased in cells from two HCC cell lines, Huh7 and HepG2, in a dose- and time-dependent manner. Phosphorylated to total ERK1/2 ratio was increased in Huh7 cells following IL-16 50 ng/ml, but not HepG2 cells. ERK phosphorylation have occurred earlier than protein accumulation at 48 h. Pretreatment with the ERK inhibitor, FR18024, or an anti-IL-16 antibody reduced the increase in IL-16 production in HCC cells. CONCLUSIONS: These results suggest that cell proliferation induced by IL-16 is mediated through the ERK pathway, thus, we identified a new factor associated with HCC tumor growth. Show more

Keywords: Antibody-based protein array, IL-16, Cyclin D1, ERK, hepatocellular carcinoma

DOI: 10.3233/TUB-211507

Citation: Tumor Biology, vol. 43, no. 1, pp. 309-325, 2021

Authors: Andrade da Mota, Tales Henrique | Reis Guimarães, Ana Flávia | Silva de Carvalho, Amandda Évelin | Saldanha- de Araujo, Felipe | Pinto de Faria Lopes, Giselle | Pittella-Silva, Fábio | do Amaral Rabello, Doralina | Madureira de Oliveira, Diêgo

Article Type: Research Article

Abstract: BACKGROUND: The inhibition of the enzyme telomerase (TERT) has been widely investigated as a new pharmacological approach for cancer treatment, but its real potential and the biochemical consequences are not totally understood. OBJECTIVE: Here, we investigated the effects of the telomerase inhibitor MST-312 on a human glioma cell line after both short- and long-term (290 days) treatments. METHODS: Effects on cell growth, viability, cell cycle, morphology, cell death and genes expression were assessed. RESULTS: We found that short-term treatment promoted cell cycle arrest followed by apoptosis. Importantly, cells with telomerase knock-down revealed that the …toxic effects of MST-312 are partially TERT dependent. In contrast, although the long-term treatment decreased cell proliferation at first, it also caused adaptations potentially related to treatment resistance and tumor aggressiveness after long time of exposition. CONCLUSIONS: Despite the short-term effects of telomerase inhibition not being due to telomere erosion, they are at least partially related to the enzyme inhibition, which may represent an important strategy to pave the way for tumor growth control, especially through modulation of the non-canonical functions of telomerase. On the other hand, long-term exposure to the inhibitor had the potential to induce cell adaptations with possible negative clinical implications. Show more

Keywords: Glioma, telomerase, TERT, MST-312, long-term treatment

DOI: 10.3233/TUB-211515

Citation: Tumor Biology, vol. 43, no. 1, pp. 327-340, 2021

Authors: Meirovitz, Amichay | Baider, Lea | Peretz, Tamar | Stephanos, Samir | Barak, Vivian

Article Type: Research Article

Abstract: BACKGROUND: Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties. MAIN OBJECTIVE: To evaluate PTX effects on colon cancer patients treated with chemotherapy. PATIENTS and METHODS: Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX). …RESULTS: Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group. CONCLUSIONS: PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence –all important parameters of cachexia. Show more

Keywords: Pentoxifylline, colon cancer, cachexia, weight gain, stomatitis, survival

DOI: 10.3233/TUB-211533

Citation: Tumor Biology, vol. 43, no. 1, pp. 341-349, 2021

Article Type: Retraction

Abstract: The publisher and the Editor-in-Chief of Tumor Biology retract a total of 15 articles from the journals’ online catalog. The articles were published in different issues of the journal during the period 2014–2016. All articles affected by this retraction notice have problems related to image manipulation or misuse. A detailed explanation is given for each retracted article. The investigations were carried out in accordance with the recommendations of the Committee on Publication Ethics (COPE).

DOI: 10.3233/TUB-219010

Citation: Tumor Biology, vol. 43, no. 1, pp. 351-354, 2021

Authors: Blackman, Alexandra | Mitchell, Jessica | Rowswell-Turner, Rachael | Singh, Rakesh | Kim, Kyu Kwang | Eklund, Elizabeth | Skates, Steven | Bast, Robert C. | Messerlian, Geralyn | Miller, M. Craig | Moore, Richard G.

Article Type: Research Article

Abstract: BACKGROUND: The measurement of serum HE4 levels has emerged as a sensitive and specific biomarker for epithelial ovarian cancers (EOCs). However, serum levels in women diagnosed with various histologic subtypes of EOC and in women with metastatic non-ovarian primary malignancies have not been widely reported. OBJECTIVE: The goal of this study was to identify how serum HE4 levels vary in women diagnosed with different histologic subtypes of EOC and non-ovarian malignancies. METHODS: Data from six prospective pelvic mass clinical trials was combined and an evaluation of serum HE4 levels in women diagnosed with a malignancy was …performed. For all patients, serum was obtained prior to surgery and final pathology, including primary tumor site, histologic subtype, grade and stage, were recorded. The mean, median, standard deviation, maximum, and minimum HE4 levels were determined for each group. RESULTS: A total of 984 patients were included in this study, with the average patient age being 60 years old. There were 230 premenopausal and 754 postmenopausal patients. Serum HE4 levels were elevated (≥70.0 pMol) in 85%of EOCs, 40%of LMP tumors, 21%of non-EOCs (germ cell tumors), 25%of cervical cancers, and 47%of non-gynecologic metastatic cancers. Analysis of histologic subtypes revealed 90%(n  = 391) of serous, 85%(n  = 73) of endometrioid, 45%(n  = 42) of mucinous, 86%(n  = 51) of mixed tumors, and 69%(n  = 36) of clear cell tumors had elevated serum HE4 levels. CONCLUSIONS: Serum HE4 levels are most often elevated in women with high grade serous and endometrioid EOCs, and though serum elevations are seen more often with advanced stage disease, HE4 is also often elevated in early stage disease and lower grade tumors. Show more

Keywords: Serum HE4, biomarker, ovarian cancer

DOI: 10.3233/TUB-211546

Citation: Tumor Biology, vol. 43, no. 1, pp. 355-365, 2021