The role of RIPK3 in the process of necroptosis in malignant tumors

Necroptosis is an alternative form of regulated cell death, combining features that apply to both apoptosis and necrosis processes. There is evidence that it is involved in regulating the balance of various cell lineages, organ formation during embryonic development, and tissue homeostasis in adults. Necroptosis plays an essential role in a number of disease processes, such as neurodegenerative diseases, myocardial ischemia, Gaucher's disease, and the progression and metastasis of a number of malignant neoplasms. The process of necroptosis can be triggered by various stimuli such as TNFα, interferon γ, lipopolysaccharides, etc. Receptor-interacting proteins (RIPKs) are serine/threonine kinases known as regulators of cell survival and death. The essence of necroptosis is in the formation of a necrosome consisting of RIPK1, RIPK3, and MLKL. The protumor and antitumor functions of necroptosis are associated with the secretion of various mediators and the initiation of an inflammatory response. Clarifying the role of necroptosis in different types of tumors would contribute to obtaining valuable information, increasing the possibilities for pharmacological influence on malignant tumors, and addressing cases of therapeutic resistance

Role of the apoptosis-inducing factor in physiological conditions and in malignant neoplasms

Apoptosis is a process of programmed cell death that functions in conditions of complex interactions with a number of other processes in the organism. It is an invariable companion in physiological life events such as growth, development, and aging. There is more and more evidence that disorders in the processes of its implementation and control are the basis of a number of pathological conditions such as autoimmune, neurodegenerative, and malignant diseases. Apoptosis is induced through a classical or alternative signaling pathway and proteins called caspases that play an essential role in cell death are being activated. Recently, a caspase-independent pathway of cell death was discovered, which is executed with the participation of mitochondria-localized apoptosis-inducing factor (AIF). During apoptosis, the protein is released into the cell cytoplasm, it undergoes conformational changes, is translocated to the nucleus with the help of macrophage migration inhibitory factor (MIF), and, as a result, cellular DNA fragmentation occurs. On the other hand, AIF takes part in the processes of oxidative phosphorylation, captures free oxygen radicals and prevents apoptosis induced by them. In a number of malignant tumors, tumor cells have acquired the ability to suppress or avoid apoptosis, which facilitates their survival and metastasis. In-depth study of the mechanisms by which neoplastic cells manage to avoid and manipulate programmed cell death is valuable and extremely important information needed to discover new approaches and drugs for therapeutic impact and overcoming treatment resistance in different types of tumors

Apoptosis and Necroptosis in Renal Cell Carcinoma // Апоптоза и некроптоза при бъбречноклетъчен карцином

RCC incidence and mortality have shown a constant tendency to increase worldwide over the years. Currently, known standard approaches for renal cell carcinoma treatment are insufficient in some cases due to resistance to chemo- and radiotherapy. Pathway activation of one or another form of cell death can be used in the search for new approaches in renal cell carcinoma treatment. There is evidence in the literature that renal carcinoma tumour cells are resistant to the intrinsic and extrinsic pathways of apoptosis. Apoptosis is programmed cell death that can also occur via another, alternative pathway that is caspase-independent and involves AIF. The role of AIF in renal cell carcinoma is poorly studied and additional research is needed, which is why it was the object of the present study. Another form of cell death is necroptosis. A key participant in the process is RIPK3, which is known to have both tumor-stimulating and tumor-suppressive functions in different tumors. Further in-depth studies are needed on the role of RIPK3 in tumour development, progression, metastases, and recurrence, as well as anti-tumour immunity in renal cell carcinoma, and its correlation with clinical-morphological indicators.Заболеваемостта и смъртността от бъбречноклетъчен карцином показват през годините една постоянна тенденция към нарастване в световен мащаб. Известните понастоящем стандартни подходи за лечение на бъбречноклетъчен карцином в някои случаи са недостатъчни поради резистентност към химиотерапия и лъчелечение. Активирането на пътищата на една или друга форма на клетъчна смърт може да бъде използвано в търсенето на нови подходи при лечението на бъбречноклетъчен карцином. В литературата има данни, че туморните клетки на бъбречния карцином са устойчиви на вътрешния и външен път на апоптоза. Апоптозата е програмирана клетъчна смърт, която може да се осъществи и по друг, алтернативен път, който е каспаза-независим и участник в него е АIF. Ролята на AIF при бъбречния карцином е слабо проучена и са необходими допълнителни изследвания, поради което той е обект на настоящото проучване. Друга форма на клетъчна смърт е некроптозата. Основен участник в процеса е RIPK3, за която е известно, че може да има както тумор-стимулираща, така и тумор-супресивна функция при различните тумори. Необходими са допълнителни задълбочени проучвания върху ролята на RIPK3 по отношение развитието на туморите, прогресията, метастазите, възникването на рецидиви, както и на анти-туморния имунитет при бъбречноклетъчния карцином, а също и на корелацията й с клинико-морфологичните показатели

Testicular mixed germ-cell tumor - seminoma, embryonal carcinoma and yolk sac tumor

Introduction: Germ-cell tumors are a heterogeneous group of neoplasms which are classified differ­ently according to different literature. Mixed germ-cell tumors are a combination of two or more his­tological types and can include a seminomatous and non-seminomatous component. The following case presents a rare mixed germ-cell tumor with the characteristics of embryonal carcinoma, semi­noma and yolk sac tumor.Methods and Materials: A 27-year-old male presented with a history of left sided scrotal pain and swelling. By self-examination the patient discovered a rounded formation in the left testicle. After a consult with an urologist the patient was referred for surgery and a high funiculo-orchiectomy was performed, due to psychologically traumatic experience an insertion of prosthesis was suggested.Results: Ultrasonography showed a capsulated hypoechoic tumor formation. Computed tomography (CT) of the chest, abdomen and pelvis revealed no evidence of lymphadenopathy and metastases. During blood tests increased levels of alpha-fetoprotein were established. Macroscopically the forma­tion was oval-shaped and solid, on the cut surface hemorrhages and necroses were observed. The bi­opsy materials showed a picture of heterogeneous three-component malignant tumor. The mass was partially consisted of atypical cells with optically empty cytoplasm forming tubular structures which demonstrated the seminomous part. The presence of Schiller-Duval bodies signified yolk sac malig­nancy. The embryonic component was represented by microcystic structures comprised of cells with hyperchromic nuclei.Conclusion: Mixed germ cell tumors sometimes contain an unusual mixture of histologic types that are important to be correctly identified in reference to the selection of an appropriate treatment and therefore getting the best results for the patient

Anorectal Melanoma - a Histopathological Case Report and a Review of the Literature

Abstract Primary melanomas of the anus and rectum are rare neoplasms with aggressive behavior, accounting for 0.1%-4.6% of anal canal tumors. Mucosal melanomas account for approximately 1.2% of all melanomas, of which fewer than 25% are anorectal. Histological evaluation with immunohistochemical stains like HMB-45, S-100, vimentin and Melan A is required for definitive diagnosis. The 5-year survival rate for anorectal melanomas (AM) was reported to be as low as &lt; 20%, in contrast to the value of approximately 80% for cutaneous melanomas. Furthermore, up to 67% of patients are found to have distant metastases at the time of their initial diagnosis with AM. Since the chemotherapy treatment possibilities are limited, patients usually undergo mutation detection tests giving the opportunity of targeted therapy. Herein we report a case of a patient with anorectal melanoma, diagnosed in stage II and the pathomorphological and mutation status finding, together with their correlation to tumor behavior and patient prognosis.</jats:p