Browsing by Subject "ADENOCARCINOMA"

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  • Hautala, Laura C.; Pang, Poh-Choo; Antonopoulos, Aristotelis; Pasanen, Annukka; Lee, Cheuk-Lun; Chiu, Philip C. N.; Yeung, William S. B.; Loukovaara, Mikko; Bützow, Ralf; Haslam, Stuart M.; Dell, Anne; Koistinen, Hannu (2020)
    Glycodelin is a major glycoprotein expressed in reproductive tissues, like secretory and decidualized endometrium. It has several reproduction related functions that are dependent on specific glycosylation, but it has also been found to drive differentiation of endometrial carcinoma cells toward a less malignant phenotype. Here we aimed to elucidate whether the glycosylation and function of glycodelin is altered in endometrial carcinoma as compared with a normal endometrium. We carried out glycan structure analysis of glycodelin expressed in HEC-1B human endometrial carcinoma cells (HEC-1B Gd) by mass spectrometry glycomics strategies. Glycans of HEC-1B Gd were found to comprise a typical mixture of high-mannose, hybrid, and complex-type N-glycans, often containing undecorated LacNAc (Gal beta 1-4GlcNAc) antennae. However, several differences, as compared with previously reported glycan structures of normal human decidualized endometrium-derived glycodelin isoform, glycodelin-A (GdA), were also found. These included a lower level of sialylation and more abundant poly-LacNAc antennae, some of which are fucosylated. This allowed us to select lectins that showed different binding to these classes of glycodelin. Despite the differences in glycosylation between HEC-1B Gd and GdA, both showed similar inhibitory activity on trophoblast cell invasion and peripheral blood mononuclear cell proliferation. For the detection of cancer associated glycodelin, we established a novel in situ proximity-ligation based histochemical staining method using a specific glycodelin antibody and UEAI lectin. We found that the UEAI reactive glycodelin was abundant in endometrial carcinoma, but virtually absent in normal endometrial tissue even when glycodelin was strongly expressed. In conclusion, we established a histochemical staining method for the detection of endometrial carcinoma-associated glycodelin and showed that this specific glycodelin is exclusively expressed in cancer, not in normal endometrium. Similar methods can be used for studies of other glycoproteins. Glycodelin is a major endometrial glycoprotein. The authors analyzed glycan structures of endometrial carcinoma associated glycodelin and established a novel glycodelin-glycoform specific histochemical staining method. With this, they showed that glycodelin is differentially glycosylated in endometrial carcinoma tissue, as compared to normal endometrium, representing a neoantigen with potential clinical applications.
  • Sobral-Leite, Marcelo; Wesseling, Jelle; Smit, Vincent T. H. B. M.; Nevanlinna, Heli; van Miltenburg, Martine H.; Sanders, Joyce; Hofland, Ingrid; Blows, Fiona M.; Coulson, Penny; Patrycja, Gazinska; Schellens, Jan H. M.; Fagerholm, Rainer; Heikkila, Paivi; Aittomaki, Kristiina; Blomqvist, Carl; Provenzano, Elena; Ali, Hamid Raza; Figueroa, Jonine; Sherman, Mark; Lissowska, Jolanta; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Phillips, Kelly-Anne; Couch, Fergus J.; Olson, Janet E.; Vachon, Celine; Visscher, Daniel; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Holleczek, Bernd; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W. M.; van Deurzen, Carolien H. M.; van de Water, Bob; Broeks, Annegien; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Easton, Douglas F.; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; de Graauw, Marjo; Schmidt, Marjanka K.; kConFab AOCS Investigators (2015)
    Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45). Conclusions: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
  • Slik, Khadija; Turkki, Riku; Carpen, Olli; Kurki, Samu; Korkeila, Eija; Sundström, Jari; Pellinen, Teijo (2019)
    Current risk factors in stage II colorectal carcinoma are insufficient to guide treatment decisions. Loss of CDX2 has been shown to associate with poor clinical outcome and predict benefit for adjuvant chemotherapy in stage II and III colorectal carcinoma. The prognostic relevance of CDX2 in stage II disease has not been sufficiently validated, especially in relation to clinical risk factors, such as microsatellite instability (MSI) status, BRAF mutation status, and tumor budding. In this study, we evaluated the protein expression of CDX2 in tumor center and front areas in a tissue microarrays material of stage II colorectal carcinoma patients (n=232). CDX2 expression showed a partial or total loss in respective areas in 8.6% and 10.9% of patient cases. Patients with loss of CDX2 had shorter disease-specific survival when scored independently either in tumor center or tumor front areas (log rank P=0.012; P=0.012). Loss of CDX2 predicted survival independently of other stage II risk factors, such as MSI status and BRAF mutation status, pT class, and tumor budding (hazard ratio=5.96, 95% confidence interval=1.55-22.95; hazard ratio=3.70, 95% confidence interval=1.30-10.56). Importantly, CDX2 loss predicted inferior survival only in patients with microsatellite stable, but not with MSI-high phenotype. Interestingly, CDX2 loss associated with low E-cadherin expression, tight junction disruption, and high expression of ezrin protein. The work demonstrates that loss of CDX2 is an independent risk factor of poor disease-specific survival in stage II colorectal carcinoma. Furthermore, the study suggests that CDX2 loss is linked with epithelial-to-mesenchymal transition independently of tumor budding.
  • Nagaraj, Ashwini S.; Lahtela, Jenni; Hemmes, Annabrita; Pellinen, Teijo; Blom, Sami; Devlin, Jennifer R.; Salmenkivi, Kaisa; Kallioniemi, Olli; Mäyränpää, Mikko; Narhi, Katja; Verschuren, Emmy W. (2017)
    Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. We studied how the cell of origin contributes to phenotypic heterogeneity following conditional expression of Kras(G12D) and loss of Lkb1 (Kras; Lkb1). Using progenitor cell-type-restricted adenoviral Cre to target cells expressing surfactant protein C (SPC) or club cell antigen 10 (CC10), we show that Ad5-CC10-Cre-infected mice exhibit a shorter latency compared with Ad5-SPC-Cre cohorts. We further demonstrate that CC10(+) cells are the predominant progenitors of adenosquamous carcinoma (ASC) tumors and give rise to a wider spectrum of histotypes that includes mucinous and acinar adenocarcinomas. Transcriptome analysis shows ASC histotype-specific upregulation of pro-inflammatory and immunomodulatory genes. This is accompanied by an ASC-specific immunosuppressive environment, consisting of downregulated MHC genes, recruitment of CD11b(+) Gr-1(+) tumor-associated neutrophils (TANs), and decreased T cell numbers. We conclude that progenitor cell-specific etiology influences the Kras; Lkb1-driven tumor histopathology spectrum and histotype-specific immune microenvironment.
  • Söderström, Henna K.; Rasanen, Jari; Saarnio, Juha; Toikkanen, Vesa; Tyrväinen, Tuula; Rantanen, Tuomo; Valtola, Antti; Ohtonen, Pasi; Pääaho, Minna; Kokkola, Arto; Kallio, Raija; Karttunen, Tuomo J.; Pohjanen, Vesa-Matti; Ristimäki, Ari; Laine, Simo; Sihvo, Eero; Kauppila, Joonas H. (2020)
    Purpose The Finnish National Esophago-Gastric Cancer Cohort (FINEGO) was established to combine the available registry data with detailed patient information to form a comprehensive, retrospective, population-based research platform of surgically treated oesophageal and gastric cancer in Finland. This cohort profile describes the 2045 surgically treated patients with oesophageal cancer included in the FINEGO cohort. Participants Registry data were collected from the National Cancer, Patient, Education and Death Registries from 1 January 1987 to 31 December 2016. All patients over 18 years of age, who had either curative surgery, palliative surgery or salvage surgery for primary cancer in the oesophagus are included in this study. Findings to date 2045 patients had surgery for oesophageal cancer in the selected time period. 67.2% were man, and the majority had only minor comorbidities. The proportions of adenocarcinomas and squamous cell carcinomas were 43.1% and 44.4%, respectively, and 12.5% had other or missing histology. Only about 23% of patients received neoadjuvant therapy. Oesophagectomy was the treatment of choice and most patients were treated at low-volume centres, but median annual hospital volume increased over time. Median overall survival was 23 months, 5-year survival for all patients in the cohort was 32.9% and cancer-specific survival was 36.5%. Future plans Even though Finland only has a population of 5.5 million, surgery for oesophageal carcinoma has not been centralised and therefore previously reported results have mostly been small, single-centre cohorts. Because of FINEGO, we now have a population-based, unselected cohort of surgically treated patients, enabling research on national trends over time regarding oesophageal cancer, including patient characteristics, tumour histology, stage and neoadjuvant treatment, surgical techniques, hospital volumes and patient mortality. Data collection is ongoing, and the cohort will be expanded to include more detailed data from patient records and national biobanks.
  • Kauppila, Joonas H.; Ohtonen, Pasi; Rantanen, Tuomo; Tyrväinen, Tuula; Toikkanen, Vesa; Pääaho, Minna; Valtola, Antti; Räsänen, Jari; Kallio, Raija; Sihvo, Eero; Saarnio, Juha; Karttunen, Tuomo J.; Pohjanen, Vesa-Matti; Ristimäki, Ari; Laine, Simo; Kokkola, Arto (2020)
    Purpose The Finnish National Esophago-Gastric Cancer Cohort (FINEGO) was established with the aim of identifying factors that could contribute to improved outcomes in oesophago-gastric cancer. The aim of this study is to describe the patients with gastric cancer included in FINEGO. Participants A total of 10 457 patients with gastric cancer or tumour diagnosis in the Finnish Cancer Registry or the Finnish Patient Registry during 1987-2016 were included in the cohort, with follow-up from Causes of Death Registry until 31 December 2016. All of the participants were at least 18 years of age, and had undergone either resectional or endoscopic mucosal surgery with curative or palliative intent. Findings to date Of the 10 457 patients, 90.1% were identified to have cancer in both cancer and patient registries. In all, the median age was 70 at the time of surgery, 54.5% of the patients were men and 64.4% had no comorbidities. Education data were available for 31.1% of the patients, of whom the majority had had
  • Saraswat, Mayank; Joenvaara, Sakari; Seppanen, Hanna; Mustonen, Harri; Haglund, Caj; Renkonen, Risto (2017)
    Finland ranks sixth among the countries having highest incidence rate of pancreatic cancer with mortality roughly equaling incidence. The average age of diagnosis for pancreatic cancer is 69years in Nordic males, whereas the average age of diagnosis of chronic pancreatitis is 40-50years, however, many cases overlap in age. By radiology, the evaluation of a pancreatic mass, that is, the differential diagnosis between chronic pancreatitis and pancreatic cancer is often difficult. Preoperative needle biopsies are difficult to obtain and are demanding to interpret. New blood based biomarkers are needed. The accuracy of the only established biomarker for pancreatic cancer, CA 19-9 is rather poor in differentiating between benign and malignant mass of the pancreas. In this study, we have performed mass spectrometry analysis (High Definition MSE) of serum samples from patients with chronic pancreatitis (13) and pancreatic cancer (22). We have quantified 291 proteins and performed detailed statistical analysis such as principal component analysis, orthogonal partial least square discriminant analysis and receiver operating curve analysis. The proteomic signature of chronic pancreatitis versus pancreatic cancer samples was able to separate the two groups by multiple statistical techniques. Some of the enriched pathways in the proteomic dataset were LXR/RXR activation, complement and coagulation systems and inflammatory response. We propose that multiple high-confidence biomarker candidates in our pilot study including Inter-alpha-trypsin inhibitor heavy chain H2 (Area under the curve, AUC: 0.947), protein AMBP (AUC: 0.951) and prothrombin (AUC: 0.917), which should be further evaluated in larger patient series as potential new biomarkers for differential diagnosis.
  • Riihimaeki, Matias; Thomsen, Hauke; Hemminki, Akseli; Sundquist, Kristina; Hemminki, Kari (2013)
  • Hagens, Eliza R. C.; Henegouwen, Mark I. van Berge; van Sandick, Johanna W.; Cuesta, Miguel A.; van der Peet, Donald L.; Heisterkamp, Joos; Nieuwenhuijzen, Grard A. P.; Rosman, Camiel; Scheepers, Joris J. G.; Sosef, Meindert N.; van Hillegersberg, Richard; Lagarde, Sjoerd M.; Nilsson, Magnus; Räsänen, Jari; Nafteux, Philippe; Pattyn, Piet; Hoelscher, Arnulf H.; Schroeder, Wolfgang; Schneider, Paul M.; Mariette, Christophe; Castoro, Carlo; Bonavina, Luigi; Rosati, Riccardo; de Manzoni, Giovanni; Mattioli, Sandro; Roig Garcia, Josep; Pera, Manuel; Griffin, Michael; Wilkerson, Paul; Chaudry, M. Asif; Sgromo, Bruno; Tucker, Olga; Cheong, Edward; Moorthy, Krishna; Walsh, Thomas N.; Reynolds, John; Tachimori, Yuji; Inoue, Haruhiro; Matsubara, Hisahiro; Kosugi, Shin-ichi; Chen, Haiquan; Law, Simon Y. K.; Pramesh, C. S.; Puntambekar, Shailesh P.; Murthy, Sudish; Linden, Philip; Hofstetter, Wayne L.; Kuppusamy, Madhan K.; Shen, K. Robert; Darling, Gail E.; Sabino, Flavio D.; Grimminger, Peter P.; Meijer, Sybren L.; Bergman, Jacques J. G. H. M.; Hulshof, Maarten C. C. M.; van Laarhoven, Hanneke W. M.; Mearadji, Banafsche; Bennink, Roel J.; Annema, Jouke T.; Dijkgraaf, Marcel G. W.; Gisbertz, Suzanne S. (2019)
    BackgroundAn important parameter for survival in patients with esophageal carcinoma is lymph node status. The distribution of lymph node metastases depends on tumor characteristics such as tumor location, histology, invasion depth, and on neoadjuvant treatment. The exact distribution is unknown. Neoadjuvant treatment and surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy has not been reached. The aim of this study is to determine the distribution of lymph node metastases in patients with resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed. This can be the foundation for a uniform worldwide staging system and establishment of the optimal surgical strategy for esophageal cancer patients.MethodsThe TIGER study is an international observational cohort study with 50 participating centers. Patients with a resectable esophageal or gastro-esophageal junction carcinoma in whom a transthoracic esophagectomy with a 2- or 3-field lymphadenectomy is performed in participating centers will be included. All lymph node stations will be excised and separately individually analyzed by pathological examination. The aim is to include 5000 patients. The primary endpoint is the distribution of lymph node metastases in esophageal and esophago-gastric junction carcinoma specimens following transthoracic esophagectomy with at least 2-field lymphadenectomy in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and (disease free) survival.DiscussionThe TIGER study will provide a roadmap of the location of lymph node metastases in relation to tumor histology, tumor location, invasion depth, number of lymph nodes and lymph node metastases, pre-operative diagnostics, neo-adjuvant therapy and survival. Patient-tailored treatment can be developed based on these results, such as the optimal radiation field and extent of lymphadenectomy based on the primary tumor characteristics.Trial registrationNCT03222895, date of registration: July 19th, 2017.
  • Björkman, Patrick; Kantonen, Ilkka; Blomqvist, Carl; Venermo, Maarit; Alback, Anders (2019)
    Aortic sarcomas have not been linked to Lynch syndrome in humans, although other soft tissue malignancies have been. We report the case of a 31-year-old man with Lynch syndrome, who presented with abdominal pain and severe claudication. The clinical and diagnostic workup revealed near occlusion of the infrarenal aorta due to aortic angiosarcoma. En bloc resection of the visceral and infrarenal aorta with right nephrectomy was performed, facilitated by temporary extracorporeal bypass to the visceral arteries. The aorta was reconstructed with a bifurcated Dacron graft. At the 24-month follow-up examination, the patient was free of disease but was experiencing chronic diarrhea.
  • Youssef, Omar; Sarhadi, Virinder; Ehsan, Homa; Böhling, Tom; Carpelan-Holmström, Monika; Koskensalo, Selja; Puolakkainen, Pauli; Kokkola, Arto; Knuutila, Sakari (2017)
    AIM To study cancer hotspot mutations by next-generation sequencing (NGS) in stool DNA from patients with different gastrointestinal tract (GIT) neoplasms. METHODS Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by using the PSP (R) Spin Stool DNA Plus Kit. For each sample, 20 ng of DNA was used to construct sequencing libraries using the Ion AmpliSeq Cancer Hotspot Panel v2 or Ion AmpliSeq Colon and Lung Cancer panel v2. Sequencing was performed on Ion PGM. Torrent Suite Software v.5.2.2 was used for variant calling and data analysis. RESULTS NGS was successful in assaying 72 GIT samples and 13 healthy controls, with success rates of the assay being 78% for stomach neoplasia and 87% for colorectal tumors. In stool specimens from patients with gastric neoplasia, five hotspot mutations were found in APC, CDKN2A and EGFR genes, in addition to seven novel mutations. From colorectal patients, 20 mutations were detected in AKT1, APC, ERBB2, FBXW7, KIT, KRAS, NRAS, SMARCB1, SMO, STK11 and TP53. Healthy controls did not exhibit any hotspot mutations, except for two novel ones. APC and TP53 were the most frequently mutated genes in colorectal neoplasms, with five mutations, followed by KRAS with two mutations. APC was the most commonly mutated gene in stools of patients with premalignant/benign GIT lesions. CONCLUSION Our results show that in addition to colorectal neoplasms, mutations can also be assayed from stool specimens of patients with gastric neoplasms.
  • Laitinen, Alli; Bockelman, Camilla; Hagstrom, Jaana; Kokkola, Arto; Kallio, Pauliina; Haglund, Caj (2017)
    Background PROX1 is a transcription factor involved in the development of various organs. It has also an important function in colorectal cancer progression. The aim of this study was to investigate the prognostic role of PROX1 expression in gastric cancer. Methods We evaluated PROX1 expression in gastric cancer by immunohistochemistry of tumor-tissue microarrays including tumor specimens from 283 patients who underwent surgery at Helsinki University Hospital. We investigated the association of PROX1 expression with clinicopathologic variables and patient survival. Results Cytoplasmic PROX1 reactivity was high in 56 (20.5%) and low in 217 (79.5%) cases. Low PROX1 immunostaining associated with diffuse cancer type (p = 0.002). In subgroup analysis, PROX1 was a significant marker of better prognosis in patients aged under 66 (p = 0.007), in those with intestinal cancer (p = 0.025), among men (p = 0.019), and in tumors of less than 5 cm diameter (p = 0.030). Patients with high PROX1 expression had a cancer-specific 5-year survival of 65.6% (95% CI 52.7-78.5), compared to 37.1% (95% CI 30.2-44.0) for those with low expression (p = 0.004, log-rank test). This result remained significant in multivariable analysis (HR = 0.56; 95% CI 0.35-0.90; p = 0.017). Conclusion In gastric cancer, high cytoplasmic PROX1 expression is an independent marker of better prognosis.
  • Cserni, Gabor; Floris, Giuseppe; Koufopoulos, Nektarios; Kovacs, Aniko; Nonni, Afroditi; Regitnig, Peter; Ståhls, Anders; Varga, Zsuzsanna (2017)
    Invasive lobular carcinoma of the breast is known to produce intracellular mucin and has been recognized in single-case reports to show extracellular mucin production, as well. This latter morphology is not only rare but must also be under- or misdiagnosed. The aim was to better characterize this entity. Cases of lobular cancers demonstrating extracellular mucin formation were identified in a multi-institutional effort and their clinical and morphologic features were assessed. Immunohistochemistry was used to characterize the E-cadherin-membrane complex, neuroendocrine differentiation, and to some extent, mucin formation. All but one of the eight cases occurred in postmenopausal patients. Extracellular mucin production was present in 5 to 50% of the tumour samples and rarely also appeared in nodal and distant metastases. The tumours were completely E-cadherin negative and showed cytoplasmic p120 positivity. The majority (n = 6/8) was also completely negative for beta-catenin, but two tumours displayed focal beta-catenin positivity in the mucinous area. MUC1 and MUC2 expression was observed in all and 7/8 tumours, respectively; neuroendocrine differentiation was present in only one. Invasive lobular carcinoma with extracellular mucin formation is a rare morphologic variant of lobular carcinoma prone to be misdiagnosed and warranting further studies.
  • Laajala, Teemu D.; Seikkula, Heikki; Sadat, Fatemeh Seyednasrollah; Mirtti, Tuomas; Bostrom, Peter J.; Elo, Laura L. (2016)
    Ultrasensitive prostate-specific antigen (u-PSA) remains controversial for follow-up after radical prostatectomy (RP). The aim of this study was to model PSA doubling times (PSADT) for predicting biochemical recurrence (BCR) and to capture possible discrepancies between u-PSA and traditional PSA (t-PSA) by utilizing advanced statistical modeling. 555 RP patients without neoadjuvant/adjuvant androgen deprivation from the Turku University Hospital were included in the study. BCR was defined as two consecutive PSA values > 0.2 ng/mL and the PSA measurements were log(2)-transformed. One third of the data was reserved for independent validation. Models were first fitted to the post-surgery PSA measurements using cross-validation. Major trends were then captured using linear mixed-effect models and a predictive generalized linear model effectively identified early trends connected to BCR. The model generalized for BCR prediction to the validation set with ROC-AUC of 83.6% and 95.1% for the 1 and 3 year follow-up censoring, respectively. A web-based tool was developed to facilitate its use. Longitudinal trends of u-PSA did not display major discrepancies from those of t-PSA. The results support that u-PSA provides useful information for predicting BCR after RP. This can be beneficial to avoid unnecessary adjuvant treatments or to start them earlier for selected patients.
  • Alburquerque-Gonzalez, Begona; Bernabe-Garcia, Manuel; Montoro-Garcia, Silvia; Bernabe-Garcia, Angel; Rodrigues, Priscila Campioni; Ruiz Sanz, Javier; Lopez-Calderon, Fernando F.; Luque, Irene; Nicolas, Francisco Jose; Cayuela, Maria Luisa; Salo, Tuula; Perez-Sanchez, Horacio; Conesa-Zamora, Pablo (2020)
    Colorectal cancer: Antitumor antidepressant The antidepressant drug imipramine can block the activity of a protein that contributes to the progression of certain aggressive tumors. Serrated adenocarcinoma (SAC) is a form of colorectal cancer with a poor prognosis. A key factor in SAC development is the overexpression of the protein fascin1, which promotes the formation of structures that help cancer cells move around, thereby leading to metastasis. Pablo Conesa-Zamora at Santa Lucia University Hospital in Cartagena, Horacio Perez-Sanchez at the Universidad Catolica de Murcia in Guadalupe, Spain, and coworkers demonstrated that imipramine shows promise in binding to fascin1 and blocking its activity. The team analyzed over 9500 compounds as potential fascin1 blockers, identifying imipramine as a possible option. In tests on human tissues and in vivo studies using zebrafish, the drug reduced cancer invasion and metastasis. Serrated adenocarcinoma (SAC) is more invasive, has worse outcomes than conventional colorectal carcinoma (CRC), and is characterized by frequent resistance to anti-epidermal growth factor receptor (EGFR) and overexpression of fascin1, a key protein in actin bundling that plays a causative role in tumor invasion and is overexpressed in different cancer types with poor prognosis. In silico screening of 9591 compounds, including 2037 approved by the Food and Drug Administration (FDA), was performed, and selected compounds were analyzed for their fascin1 binding affinity by differential scanning fluorescence. The results were compared with migrastatin as a typical fascin1 inhibitor. In silico screening and differential scanning fluorescence yielded the FDA-approved antidepressant imipramine as the most evident potential fascin1 blocker. Biophysical and different in vitro actin-bundling assays confirm this activity. Subsequent assays investigating lamellipodia formation and migration and invasion of colorectal cancer cells in vitro using 3D human tissue demonstrated anti-fascin1 and anti-invasive activities of imipramine. Furthermore, expression profiling suggests the activity of imipramine on the actin cytoskeleton. Moreover, in vivo studies using a zebrafish invasion model showed that imipramine is tolerated, its anti-invasive and antimetastatic activities are dose-dependent, and it is associated with both constitutive and induced fascin1 expression. This is the first study that demonstrates an antitumoral role of imipramine as a fascin1 inhibitor and constitutes a foundation for a molecular targeted therapy for SAC and other fascin1-overexpressing tumors.
  • Dang, Kien Xuan; Ho, Tho; Sistonen, Saara; Koivusalo, Antti; Pakarinen, Mikko; Rintala, Risto; Stenman, Ulf-Hakan; Orpana, Arto; Stenman, Jakob (2018)
    Background Previous studies have reported an association among esophageal atresia (EA), Barrett's esophagus, and esophageal adenocarcinoma later in life. Objective The objective of the article is to evaluate KRAS and BRAF mutations as potential genetic markers for early detection of malignant transformation, we used an ultrasensitive technique to detect tissue expression of KRAS and BRAF mutations in endoscopic biopsies from 61 adult patients under follow-up after treatment for EA. Materials and Methods RNA was extracted from 112 fresh-frozen endoscopic tissue biopsies from 61 adult patients treated for EA in early childhood. RNA was reverse transcribed using the extendable blocking probe reverse transcription method. KRAS codons 12 and 13, as well as BRAF mutations were detected by quantitative polymerase chain reaction. Results No mutations of KRAS codon 12, KRAS codon 13, or BRAF were found in 112 endoscopic biopsy samples from 61 patients. Conclusion Despite the presence of histological findings indicating long-standing gastroesophageal reflux in 25%, as well as symptomatic gastroesophageal reflux in more than 40%, there was no detectable tissue expression of KRAS or BRAF mutations in this cohort of patients.
  • Montoro-Garcia, Silvia; Alburquerque-Gonzalez, Begona; Bernabe-Garcia, Angel; Bernabe-Garcia, Manuel; Rodrigues, Priscila Campioni; den-Haan, Helena; Luque, Irene; Jose Nicolas, Francisco; Perez-Sanchez, Horacio; Luisa Cayuela, Maria; Salo, Tuula; Conesa-Zamora, Pablo (2020)
    Tumor invasion and metastasis involve processes in which actin cytoskeleton rearrangement induced by Fascin1 plays a crucial role. Indeed, Fascin1 has been found overexpressed in tumors with worse prognosis. Migrastatin and its analogues target Fascin1 and inhibit its activity. However, there is need for novel and smaller Fascin1 inhibitors. The aim of this study was to assess the effect of compound G2 in colorectal cancer cell lines and compare it to migrastatin in in vitro and in vivo assays. Molecular modeling, actin-bundling, cell viability, inmunofluorescence, migration, and invasion assays were carried out in order to test anti-migratory and anti-invasive properties of compound G2. In addition, the in vivo effect of compound G2 was evaluated in a zebrafish model of invasion. HCT-116 cells exhibited the highest Fascin1 expression from eight tested colorectal cancer cell lines. Compound G2 showed important inhibitory effects on actin bundling, filopodia formation, migration, and invasion in different cell lines. Moreover, compound G2 treatment resulted in significant reduction of invasion of DLD-1 overexpressing Fascin1 and HCT-116 in zebrafish larvae xenografts; this effect being less evident in Fascin1 known-down HCT-116 cells. This study proves, for the first time, the in vitro and in vivo anti-tumoral activity of compound G2 on colorectal cancer cells and guides to design improved compound G2-based Fascin1 inhibitors. Key messages center dot Fascin is crucial for tumor invasion and metastasis and is overexpressed in bad prognostic tumors. center dot Several adverse tumors overexpress Fascin1 and lack targeted therapy. center dot Anti-fascin G2 is for the first time evaluated in colorectal carcinoma and compared with migrastatin. center dot Filopodia formation, migration activity, and invasion in vitro and in vivo assays were performed. center dot G2 blocks actin structures, migration, and invasion of colorectal cancer cells as fascin-dependent.
  • Vohlonen, Ilkka Juhani; Hakama, Matti; Harkonen, Matti; Malila, Nea; Pukkala, Eero; Koistinen, Veli; Sipponen, Pentti (2018)
  • FinnProstate Grp; Hackman, Greetta; Taari, Kimmo; Tammela, Teuvo L.; Matikainen, Mika; Kouri, Mauri; Joensuu, Timo; Luukkaala, Tiina; Salonen, Arto; Isotalo, Taina; Petas, Anssi; Hendolin, Niilo; Boström, Peter J.; Aaltomaa, Sirpa; Lehtoranta, Kari; Hellström, Pekka; Riikonen, Jarno; Korpela, Merja; Minn, Heikki; Kellokumpu-Lehtinen, Pirkko-Liisa; Pukkala, Eero; Hemminki, Akseli (2019)
    Background: It remains unclear whether patients with positive surgical margins or extracapsular extension benefit from adjuvant radiotherapy following radical prostatectomy. Objective: To compare the effectiveness and tolerability of adjuvant radiotherapy following radical prostatectomy. Design, setting, and participants: This was a randomised, open-label, parallel-group trial. A total of 250 patients were enrolled between April 2004 and October 2012 in eight Finnish hospitals, with pT2 with positive margins or pT3a, pN0, M0 cancer without seminal vesicle invasion. Intervention: A total of 126 patients received adjuvant radiotherapy at 66.6 Gy. Outcome measurements and statistical analysis: The primary endpoint was biochemical recurrence-free survival, which we analysed using the Kaplan-Meier method and Cox proportional hazard regression. Overall survival, cancer-specific survival, local recurrence, and adverse events were secondary endpoints. Results and limitations: The median follow-up time for patients who were alive when the follow-up ended was 9.3 yr in the adjuvant group and 8.6 yr in the observation group. The 10-yr survival for biochemical recurrence was 82% in the adjuvant group and 61% in the observation group (hazard ratio [HR] 0.26 [95% confidence interval {CI} 0.14-0.48], p <0.001), and for overall survival 92% and 87%, respectively (HR 0.69 [95% CI 0.29-1.60], p = 0.4). Two and four metastatic cancers occurred, respectively. Out of the 43 patients with biochemical recurrence in the observation group, 37 patients received salvage radiotherapy. In the adjuvant group, 56% experienced grade 3 adverse events, versus 40% in the observation group (p = 0.016). Only one grade 4 adverse event occurred (adjuvant group). A limitation of this study was the number of patients. Conclusions: Adjuvant radiotherapy following radical prostatectomy is generally well tolerated and prolongs biochemical recurrence-free survival compared with radical prostatectomy alone in patients with positive margins or extracapsular extension. Patient summary: Radiotherapy given immediately after prostate cancer surgery prolongs prostate-specific antigen progression-free survival, but causes more adverse events, when compared with surgery alone. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
  • Talwelkar, Sarang S.; Nagaraj, Ashwini S.; Devlin, Jennifer R.; Hemmes, Annabrita; Potdar, Swapnil; Kiss, Elina A.; Saharinen, Pipsa; Salmenkivi, Kaisa Maria; Mäyränpää, Mikko I.; Wennerberg, Krister; Verschuren, Emmy (2019)
    Most non-small cell lung cancers (NSCLC) contain nontargetable mutations, including KRAS, TP53, or STK11/LKB1 alterations. By coupling ex viva drug sensitivity profiling with in vivo drug response studies, we aimed to identify drug vulnerabilities for these NSCLC subtypes. Primary adenosquamous carcinoma (ASC) or adenocarcinoma (AC) cultures were established from Kras(G12D/+);Lkb1(fl/fl) (KL) tumors or AC cultures from Kras(G12D/+);p53(fl/fl) (KP) tumors. Although p53-null cells readily propagated as conventional cultures, Lkb1-null cells required conditional reprograming for establishment. Drug response profiling revealed short-term response to MEK inhibition, yet long-term clonogenic assays demonstrated resistance, associated with sustained or adaptive activation of receptor tyrosine kinases (RTK): activation of ERBBs in KL cultures, or FGFR in AC niltures. Furthermore, pan-ERBB inhibition reduced the clonogenidty of KL cultures, which was exacerbated by combinatorial MEK inhibition, whereas combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, in vivo studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of in situ ERBB signaling networks in conjunction with ex vivo drug response profiling and biochemical dissection of adaptive RTK activities may serve as a valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.