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Jan 2022 DOI 10.14302/issn.2372-6601.jhor-22-4061
B. Danilova AnnaCorresponding author
N.N. Petrov National Medicine Research Center of Oncology, Department of Oncoimmunology, 197758, Leningradskaya str., 68, Pesochny, Saint-Petersburg, Russian Federation
Background Human malignant cell models which reflect the structural and physiological complexity of tumor tissue are of great importance for preclinical research in oncology. Spheroids/tumoroids derived from solid tumors are of great interest as cellular models mimicking the first vascular-free growth phase of a tumor node. The fact of the identity between artificially created tumor multicellular aggregates and the real tumor tissue, however, needs to be specified, described and validated in order to see how closely the spheroids are biologically similar to the malignized tissues in vivo compared to the monolayer cell cultures traditionally used. We present here a comparison study of the characteristics of solid tumor cells of different histogenesis (melanomas, soft tissue sarcomas and bone sarcomas, epithelial tumors) cultured in two dimensions (monolayer culture) and three dimensional space (spheroid), namely: spatial organization, multiplication, metabolic activity. Patients and Methods For the creation of 2 D and 3D cell models the cells isolated from the patient's solid tumor fragments obtained intraoperatively were used. 15 samples of skin melanoma, 20 samples of soft tissue and osteogenic sarcomas (STBS), and 9 samples of epithelial tumors (ET). The tumor cells were all cultivated for at least 10 passages. We used phase contrast, confocal microscopy, and immunohistochemistry to investigate spheroids and monolayer cultures. The supernatants of tumor cells grown in 2D and 3D cultures were studied using ELISA and multiplex analysis for the production of a spectrum of chemokines and cytokines supporting the immunosuppression, invasion and metastasis processes. Results Tumor specimens received were predominantly of metastatic origin (75%). In 100% of cases 2D cultures were received, in 88.6% of cases (39 out of 44) we succeeded in obtaining spheroids. There was no direct correlation between the efficiency of tumoroid formation and the tumor's histogenetic origin and the stage of the cancer process (primary tumor, recurrence, metastasis). The median size of spheroids by 4-5 days of cultivation with a starting concentration of 10000 cells per well was 657.14 μm for melanoma (min 400 - max 1000 μm), 571.42 μm (min 400 - max 700 μm), 507.14 μm (min 300 - max 600 μm) for soft tissue sarcomas, 650.0 μm (min 400 - max 900 μm) for osteogenic sarcomas. Immunochemical analysis of Ki-67, GLUT1, and Ecadherin markers was carried out for tumor tissue samples, single-layer tumor cultures, and tumoroids of every patient. The distribution of the stained groups in the spheroids was distinct from the monolayer cultures and more in accordance with the distribution of such in the tissue tumor, the number of Ki-67+ cells was increasing in the spheroids. We detected no dependence of Ki-67+ and GLUT1+ cell localization grade on spheroid size. We identified E-cadherin in tumor tissue and tumoroids of breast carcinoma and one melanoma culture. Monolayer cultures did not express it. The increase in secretory cell activity of the solid tumor cells from 2D to 3D system was observed when CCL2, CCL3, CXCL1, CXCL16, MIF, IL10, MICA (p<0.01) were investigated. Conclusion The presence of patient-specific cells of solid tumors in a 3D environment causes activation of the proliferative and metabolic processes as compared to monolayer cultures, which makes these models approximate the real world clinical picture. The production of chemokines that can attract to the tumor various types of immune system cells, to include their immature versions, as well as production of cytokines and Immunosuppression factors that, when present in the tumor microenvironment in the high concentrations, contribute to the formation of immune cells having suppressive capacities occurs in the 3D cell system. Three-dimensional model of the initial tumor nodule formation stage thus demonstrates the forming process of tumor cells favorable for them microenvironment. Construction of three-dimensional models - spheroids of tumor cells of differing histogenesis demands individual approach and more thorough investigation.
May 2026 DOI 10.14302/issn.2572-3030.jcgb-26-6307
Faisst Arne-C.Corresponding author
The development of tumor biomarkers derived from blood, or its components, has become pivotal in advancing early cancer diagnosis. Malignant transformations induce cancer-specific alterations in the transcriptome, proteome, and secretome of tumor cells. Recent studies highlighted similar alterations in peripheral blood mononuclear cells (PBMCs) in cancer patients, which appear to mirror the state of transformation in tumor cells. These findings suggest an intercellular communication–driven mechanism rather than a systemic inflammatory response and, in addition to current ctDNA-based liquid biopsy biomarkers, point to a novel, simple, and highly robust approach for the early detection of cancer. Using this phenomenon to advance PBMC-based biomarker development, it will be essential to achieve 3D in vitro tumor models that reproduce a highly physiological tumor microenvironment (TME). Likewise, more enhanced 3D ex vivo models are required to enable the replication of cell-to-cell and organ-to-organ communication. These systems will guide the self-organization of mixed microenvironments derived from different tissues and enable them to accurately reproduce the molecular connections underlying these alterations. In this study, an innovative new modular 3D co-culturing approach was used to expose PBMCs to lung tumoroids, under physiologically relevant conditions. Changes in DNA fragmentation of PBMCs in the presence of lung cancer were quantified and used as a biomarker. To validate the predictiveness of this biomarker, our results were compared with clinical data from a clinical evaluation study. Similar to the clinical trial observations, PBMCs, when exposed to lung tumoroids, showed a significantly lower level of DNA fragmentation (37%). This modular 3D co-culturing model showed a predictiveness of the clinical data of > 90%, demonstrating its power to monitoring cell-to-cell communication effects and support the development of blood-based biomarkers.
Dec 2022 DOI 10.14302/issn.2574-4526.jddd-22-4151
Darouichi M.Corresponding author
Institute Medical Champel, 1206.Champel, Geneva, Switzerland
Steroid cell tumors of the ovary are particularly rare, secreting sex hormones, characterized by steroid cell proliferation and represent only 0.1% of all ovarian tumors. They are classified into three subtypes according to their cell of origin: stromal luteoma, Leydig cell tumors and a third subtype of unknown lineage corresponds to a not specified steroid cell tumor (SCT-NOS). This third subtype accounts for 60% of steroid cell tumors. The clinical manifestations of SCT-NOS can take many forms, including pain, abdominal distension, but perhaps the most visible presentations are those related to hormonal activity and virilization of the tumor. We present a rare case of a 48-year-old woman with vaginal bleeding and a history of trunk obesity, hirsutism for 2 years and hypothyroidism with hormone replacement therapy. Clinical examination revealed a characteristic of obesity, virilization. Serum testosterone was 3.62 µg / L and CA-125 was 40.67. Magnetic resonance imaging identified a left ovarian solid mass and histopathology confirmed a steroid cell tumor not specific. The patient underwent exploratory laparotomy and left salpingoophorectomy. Macroscopically, the mass is well circumscribed, solid, homogeneous and yellowish. Microscopically, the tumor is mainly composed of eosinophilic or vacuolar granular cytoplasm. Immunohistochemistry showed that the tumor cells were strongly positive for inhibin. The postoperative period was uneventful. Through this rare observation, we will discuss the aspects that characterize this type of tumor and present some guidelines to be used in the differential diagnosis, as well as the difficulties encountered in the clinical, radiological and therapeutic fields.
Feb 2022
Gobato RicardoCorresponding author
Green Land Landscaping and Gardening, Seedling Growth Laboratory, 86130-000, Parana, Brazil.
Using samples of small cell lung tumors, a research team led by biologist Dr. Raymond discovered two new ways to induce tumor cell death. By activating ferroptosis, one of two subtypes of tumor cells can be targeted: first, iron-dependent cell death due to oxidative stress, and second, oxidative stress. Therefore, cell death can also be induced in a different way. Both types of cell death must be caused by drugs at the same time to eliminate the majority of the tumor mass. It is currently in clinical trials for cancer treatment. Auranofin, which inhibits the production of protective antioxidants in cancer cells, has been used to treat rheumatoid arthritis for decades. Future clinical trials using this combination therapy will determine the extent to which this targeted treatment option improves the prognosis of small cell lung cancer patients. It is currently in clinical trials for cancer treatment. Lung cancer is the leading cause of cancer death in the United States. Despite evidence of molecular abnormalities in biological specimens, progress in this disease is hampered by the lack of diagnostic markers useful for clinical practice. The majority of patients with lung cancer are still diagnosed at an advanced stage, when prognosis is poor. This article reviews new strategies being studied for the early detection of lung cancer. These strategies involve new methods of imaging (including low-dose computed tomography CT scanning), DNA analysis, and proteomic-based techniques. These strategies have not only improved our understanding of lung cancer but show promise in offering better survival to patients with this deadly disease. Of paramount importance in the search for methods of early detection is the need for the identification of the ideal population to screen, a multidisciplinary approach, and validation of promising techniques.
Feb 2021 DOI 10.14302/issn.2372-6601.jhor-21-3733
Qing XinCorresponding author
Department of Pathology, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA.
Breast implant-associated anaplastic large cell lymphoma (ALCL) is a recently recognized type of T-cell lymphoma that can develop following breast implants, with morphologic and immunophenotypic features indistinguishable from those of ALK-negative ALCL. Here we report a case of a 58-year-old woman with a history of subglandular silicone implants placed for bilateral breast augmentation 25 years ago, who presented with bilateral breast pain and was found to have bilateral Baker Grade III capsular contracture, and heterogenous fluid collection centered near the left third costochondral articulation, a suspicious left chest wall lesion, and left axillary lymphadenopathy on imaging. A left axillary lymph node core biopsy and an aspiration of the fluid were performed, and no malignant cells were identified. The patient underwent bilateral removal of breast implants and total capsulectomies. Microscopic examination of the capsule surrounding the left breast implant revealed large pleomorphic tumor cells in a fibrinous exudate. By immunohistochemistry, the tumor cells were found to be positive for CD3 (subset), CD4, CD7, CD30 (strong and uniform), and CD43, and negative for CD2, CD5, CD8, and ALK1, supporting the diagnosis of breast implant-associated ALCL. No lymphoma cells were identified in the right breast capsule, confirmed by CD30 stain. Breast implant-associated ALCL is a very rare disease that can develop many years after breast implant placement. Proper evaluation with breast imaging and pathologic workup is essential to confirm the diagnosis in suspected cases. Our case highlights that adequate sampling is important in the investigation of patients with suspected breast implant-associated ALCL.
Jul 2020 DOI 10.14302/issn.2575-1212.jvhc-20-3434
R.R. Moreira PamelaCorresponding author
Background The mammary glands are the second most common tumor development site in female dogs. One of the ways of staging such tumors is to evaluate the presence or absence of distant metastasis, including in bone marrow. Such findings in human medicine are associated with poor survival of women with breast tumors. However, in veterinary medicine, this clinical staging is used more for patients with lymphomas and mastocytomas. Studies using bone marrow biopsies as a staging method for mammary tumors are scarce. Objectives The present study was to evaluate mammary lesions and bone marrow in 23 female dogs, searching for disseminated tumor cells or metastatic foci. Results: Grade I carcinoma in mixed tumors was the type most observed (22.4%), and there was no statistical difference in relation to tumor size or presence of metastasis in lymph nodes. In the bone marrow of one female dog with carcinosarcoma (4.35%), there was cytoplasmic marking of a probable disseminated tumor cell of epithelial origin, and immunohistochemical evaluation showed presence of cytokeratin-19 antibodies. None of the female dogs presenting reduced cellularity or medullary fibrosis, confirmed through Masson’s trichrome technique, had cell marking in immunohistochemical analyses. Conclusions Bone marrow evaluation can be used as a staging method for mammary gland tumors in female dogs, since disseminated tumor cells present the potential to become secondary lesions and to disseminate to distant foci, thereby causing tertiary metastases over an indeterminate period of time.
Mar 2020 DOI 10.14302/issn.2372-6601.jhor-20-3235
Sangaré-Bamba MahawaCorresponding author
Hematology Unit, Central Laboratory, Teaching Hospital of Yopougon, Côte d’Ivoire
Introduction Acute leukaemia are the clonal and malignant proliferation of immature hematopoietic cells (blast), blocked in their differentiation process. There is an interaction between cancer cells and the clotting process. This could be the expression of Tissue Factor (TF) on the surface of tumor cells; or a lesion of the vascular endothelium and platelet activation. The result is an activation of clotting that can lead to disseminated Intravascular Coagulation (DIC). The objective of this study was to assess the risk of DIC occurring in patients with acute leukaemia. Methods This was a cross-sectional study for analytical purposes that took place on 40 frozen samples from the biobank of the haematology laboratory of Teaching Hospital Yopougon for which the diagnosis of acute leukaemia had been taken from myelogram. The myelogram results were accompanied by hemogram data. PTTa, QT, fibrinogen and D-Dimers were performed on these samples. The risk assessment of DIC occurred was determined on the recommendations of the International Society of Thrombosis and Hemostasis (ISTH). Results We noted a female predominance with a Sex Ratio (M / F) of 0.90. The average age of the patients was 38 years (± 23 years) with extremes ranging from 2 to 84 years. ALL represented 20 % of cases against 80 % for AMLs. Hemogram parameters were characterized by severe anaemia (Tx Hb < 6 g / dL) in 52.5 % of cases; hyperleukocytosis > 100.103 / mm3 in 35 % of cases; thrombocytopenia < 25.103 / mm3 in 40 % of case; and significant blood and spinal cord blastosis (> 80 %). The lengthening of the PTTa was observed in 50 % of cases, compared to 40% for the QT. Similarly, hyperfibrinemia was present in 65% of cases. D-Dimers were high in almost all subject (95 % of cases). According to the ISTH criteria, 17.5 % of subjects were at risk of developing a DIC. Conclusion The risk of occurrence of DIC is indeed present during acute leukaemia. The parameters of haemostasis are thus found to be crucial data in the follow-up assessment during the diagnosis of acute leukaemia.
Feb 2020 DOI 10.14302/issn.2381-862X.jwrh-19-3143
Vishwanath Prasad PramodCorresponding author
Center for Biomedical Research, Population Council, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
Emergence of various nanoscale drug carrier platforms as Drug Delivery Systems (DDS) has revolutionized the field of medicine.Nonetheless, theside-effects due to non-specific distribution of anticancer therapeutics in normal, healthy tissues remain to be a prime pitfall in curing cancers. Therefore, to achieve a better therapeutic efficacy, the use of a target-specific delivery, combined with a stimuli-responsive nanocarrier system, particularly pH-sensitive nanosystems offer an attractive strategy. Targeted drug delivery through pH-sensitive nanosystems offer the potential to enhance the therapeutic index of anticancer agents, either by increasing the drug concentration in tumor cells and/or by decreasing the exposure in normal host tissues. Therefore, nanoscale-based drug delivery through pH-sensitive nanosystems seem to be a boon for treating gynaecological cancers (as well as other cancers) without side-effects or with least harm to normal healthy tissues.
Dec 2019 DOI 10.14302/issn.2575-1212.jvhc-19-3101
Rodrigues Reina Moreira PamelaCorresponding author
Department of Veterinary Pathology, UNESP – FCAV – Faculdade de Ciências Agrárias e Veterinárias, Jaboticabal city, São Paulo State, Brazil.
Papillary carcinoma is a mammary neoplasia of women and female dogs characterized by papillary fibrovascular projections lined by epithelial cells. Evaluation on the biology of these tumors can be done by immunohistochemistry through detection of alpha-smooth muscle actin protein in the papillary myoepithelium, which lacks such a molecule during malignant proliferations. Thus, this study aimed at determining the malignancy degree of papillary mammary tumors of female dogs by immunohistochemistry. Twenty samples of mammary neoplastic tissues collected from female dogs treated in the Veterinary Hospital at FCAV were evaluated by Hematoxylin and Eosin staining (H&E) and tumor cells were immunolabelled with monoclonal antibody to alpha-smooth muscle actin (α-SMA). Five out of 20 cases showed positive immunolabeling greater than 10% of the total immunolabeling. The remaining fourteen cases presented immunostaining lesser than 10% showing decrease or absence of α-SMA labeling in the myoepithelium of the papilla tumors. All those cases in which immunostained cell was over 10% of the neoplasm (5 immunostains of 20 total cases) were classified as benign whereas those below 10% of immunostained in the slid were considered as malignant. Therefore, immunohistochemistry played an essential role in differentiating benign and malignant papillary tumors of bitches as already described for female. Tumor classification by conventional methods, such as H&E staining, can lead to erroneous interpretations on the real biological behavior of the papillary mammary tumor.
Oct 2019 DOI 10.14302/issn.2372-6601.jhor-19-2986
Riede IsoldeCorresponding author
Independent Cancer Research, Im Amann 7, Ueberlingen D-88662.
With the definition of four gene classes, all differences between tumor cells and normal cells can be explained. Proliferative mutations induce a shortcut, forcing the cell to divide. They allow replication without control, induce somatic pairing defects of chromosomes and genome instability. Intact Tumor Supressors or mutant Switch Functions can inhibit this process. Oncogene mutations optimize the growth of the cells.
Mar 2018
Rizzello LorisCorresponding author
Department of Chemistry, University College London (UCL), 20 Gordon Street, WC1H 0AJ - London (UK)
The crusade against cancer has a new army: immunotherapy. The rational design is very simple, but brilliant at the same time. Extract the patients T-cells, reprogram them in vitro for the expression of highly specific receptors against cancer, perfuse them back to the patient. As a result, T-cells are now instructed to selectively kill circulating tumor cells, while avoiding potential side effects. This ‘Fairy Tale’ however does not lack of drawbacks and limitations. First, malignant progression can be accompanied by profound immune suppression, which counteracts the immune system-mediated tumor elimination. Second, the immune cells modification does not match high standards in terms of safety for humans. Here, nanotech can fill these gaps, and help immunotherapy to be safer and more effective.
Jul 2017 DOI 10.14302/issn.2575-1212.jvhc-17-1586
Caroline ROSOLEM MayaraCorresponding author
Students of the Postgraduate Program in Veterinary Medicine, Universidade Estadual Paulista “Júlio de Mesquita Filho” (Unesp) Faculdade de Ciências Agrárias e Veterinárias (FCAV), Campus de Jaboticabal, São Paulo, Brasil.
The mammary tumor is one of the most common cancer in female dogs and, at the present days, there is a big focus on the study of the relation between this kind of tumor in animals and the cells that stay around them, like the inflammatory cells. The objective of this study was to evaluate and show where the inflammatory cells stay in simple mammary carcinomas in female dogs by immunohistochemistry. Samples of simple mammary carcinomas (tumor group; n=26) and mammary gland samples without tumor (control group; n=18) were submitted to immunohistochemical analysis for the detection of T lymphocytes, macrophages, plasma cells and the MHC-II molecule. The mast cells were evaluated by the histochemical technique (toluidine blue). Lymphocytes, macrophages and mast cells were observed distributed in the tumor stroma. MHC-II was detected in tumor cells and in the inflammatory infiltrate. Plasma cells predominated in the peritumoral stroma. Macrophages differed significantly between the two groups and predominated in the tumor group. In the comparison between histological types of mammary carcinomas, mast cells differed significantly between solid tumors of the tubular / papillary types. The cytoplasmic immunodetection of MHC-II was suggested an inefficient antigen presentation. Some of the leukocytes present in the tumor infiltrate, appear to be exerting a pro-tumor effect and allowing the progression of tubular and papillary carcinomas. But in solid carcinomas (may be poorly immunogenic), as they had the lowest proportion of leukocytes present in the tumor site. More studies are necessary to confirm these results, such as the determination of the cytokine profile and the predominant leukocyte subpopulations in the tumor microenvironment.
Apr 2017 DOI 10.14302/issn.2372-6601.jhor-17-1463
Szablewska SylwiaCorresponding author
Nicolaus Copernicus University, Faculty of Health Sciences; Department of Oncology, Radiotherapy and Ginecologic Oncology, Poland
Melanoma is considered to be a very aggressive cancer due to its rapid growth, early and multiple metastases and limited response to standard treatment. Many researchers have hypothesized that the combination of radiation therapy and immunotherapy in the treatment of melanoma primary tumors and metastases improves the efficiency of these methods as compared to their use separately. Therefore, combined therapy is an increasingly popular topic in radiation oncology. Although the mechanism of immune response to ionizing radiation remains unclear, known are the factors involved in the immune response, including NK and CD8(+) T cells. Many studies have demonstrated the importance of inflammatory factors, primarily cytokines, in the response to ionizing radiation. In turn, many cytokines released in an irradiated organ, such as tumor necrosis factor α (TNFα), interleukins IL1 and IL6 and transforming growth factor beta (TGFβ), can induce the production of significant amounts of reactive oxygen species that are associated with the induction of DNA damage in tumor cells. In relation to anticancer immunotherapy, the clinical data obtained to date can encourage future studies combining radiation therapy and the inhibitors of cell division checkpoints in the treatment of advanced melanoma. In a recent study, melanoma cell lines became more sensitive to radiation after BRAF inhibition, which provides a potential synergistic mechanism of BRAF inhibitor (BRAFi) combined with radiation therapy for better effects of treatment. In this article, we present a systematic review of the literature on the use of the combination of radiation therapy and immunotherapy in the treatment of melanoma.
Feb 2016 DOI 10.14302/issn.2574-4496.jtc-15-838
Christophe DanielCorresponding author
IBMM, Biopark Charleroi Brussels South, B-6041 Gosselies, Universite Libre De Bruxelles, Institut De Recherche Interdisciplinaire En Biologie Humaine Et Moleculaire (IRIBHM)
Thyroid transcription factor-1 (TTF-1) is known to play key roles in thyroid organogenesis, in thyroid cell proliferation and in the expression of genes involved in thyroid differentiated function. Many human thyroid cancer cell lines keep producing TTF-1 despite the loss of differentiated gene expression, raising a question about the role of the factor in these cells. In order to investigate this point, we used a chimeric protein acting as a functional antagonist of TTF-1 transcriptional activity that was expressed conditionally in 8505C cells originating from an anaplastic thyroid carcinoma. We observed a growth arrest of 8505C thyroid cancer cells when the endogenous TTF-1 transcriptional activity was inhibited. It correlated with decreased levels of several mRNAs encoding positive effectors of cell proliferation like CDK1 and cyclinB1, and increased levels of various mRNAs encoding negative regulators of cell division like CDKN2B and DUSP6. In conclusion, the persistence of TTF-1 expression observed in the dedifferentiated human thyroid cancer cell line 8505C reflects the need of TTF-1 activity for the proliferation of these tumor cells.