Magdalena Szaryńska

Bradykinin (BK) is a biologically active nanopeptide that plays a crucial role within the kallikrein–kinin system (KKS), a complex network involved in the regulation of vascular tone, epithelial cell ion transport, vascular permeability, mucosal secretion, release of cytokines from leukocytes among others. Over the past decades, BK has attracted sustained scientific interest due to its pleiotropic effects observed across various tissues and pathological conditions. Recent advances have significantly broadened our understanding of BK’s role in modulating inflammatory and immune processes. Notably, accumulating evidence indicates that BK can exert dual and context-dependent effects—either pro-inflammatory or anti-inflammatory—depending on the cellular environment, receptor subtype activation (BK1R vs BK2R), and crosstalk with other signaling pathways. Emerging studies highlight that BK receptors may interact with another surface molecules expressed on immune cells, including T cell receptors (TCR) and immune checkpoint proteins such as PD-L1. These interactions suggest that BK signaling may be in a center of crucial immunoregulatory mechanisms influencing leukocyte activation status. Such findings may have important implications for understanding immune homeostasis and for designing novel therapeutic strategies. In cancer, BK is suggested to contribute to tumor progression through the promotion of cancer stem cells and immunosuppressive microenvironment formation, whereas in autoimmune diseases, its modulation could attenuate excessive immune activation and tissue damage. Therefore, the dual nature of BK action positions it as both a potential therapeutic target and a modulatory agent depending on disease context. This review summarizes current knowledge on the multifaceted roles of BK in inflammation and immunity, emphasizing its molecular mechanisms, receptor dynamics, and potential therapeutic applications. Special attention is given to the interplay between BK signaling and regulatory membranous proteins, offering a framework for future research aimed at exploiting BK pathways to either suppress chronic inflammation or overcome tumor-associated immunosuppression.

Colorectal cancer (CRC) is one of the most lethal malignancies worldwide, so the attempts to find novel therapeutic approaches are necessary. The aim of our study was to analyze how chemical modifications influence physical, chemical, and biological properties of the two peptides, namely, bradykinin (BK) and neurotensin (NT). For this purpose, we used fourteen modified peptides, and their anti-cancers features were analyzed on the HCT116 CRC cell line. Our results confirmed that the spherical mode of a CRC cell line culture better reflects the natural tumour microenvironment. We observed that the size of the colonospheres was markedly reduced following treatment with some BK and NT analogues. The proportion of CD133+ cancer stem cells (CSCs) in colonospheres decreased following incubation with the aforementioned peptides. In our research, we found two groups of these peptides. The first group influenced all the analyzed cellular features, while the second seemed to include the most promising peptides that lowered the count of CD133+ CSCs with parallel substantial reduction in CRC cells viability. These analogues need further analysis to uncover their overall anti-cancer potential.

Cancer stem cells (CSCs) play a key role in the development and progression of colorectal cancer (CRC), but the influence of triiodothyronine (T3) on the biological regulation of CSCs remains unclear. In the present study, it was reported that T3 exerts significant impact on CSCs of two CRC cell lines cultured in the form of colonospheres. It was observed that the incubation of colonospheres with T3 decreased the viability, proliferative and spherogenic potential of cancer cells (P<0.05). In addition, increased apoptotic rate of CRC cells treated with T3 was revealed. Furthermore, T3‑treated colonospheres were more likely to move into silenced pool in G0/G1 phase of the cell cycle. The smaller sizes of colonospheres observed after the treatment with T3 confirmed this conclusion. T3 could lower the proportion of primitive cells which supply the pool of proliferating cells within spheres. Thyroid receptors THRα1 and THRβ1 and two deiodinases (DIO2 and DIO3) were affected by T3 in manner depended on clinical stage of cancer and CRC cell line used for analysis. In summary, the present study uncovered a novel function of thyroid hormones signaling in the regulation of the CSCs of CRC, and these findings may be useful for developing novel therapies by targeting thyroid hormone functions in CRC cells.

Cancer cells, especially cancer stem cells (CSCs), are known for their therapeutic resistance and ability to induce a cancer relapse even many years after successful treatment. The quest for a novel protocol utilizing some commonly used non-oncologic drugs that would improve patients outcomes seems to be the right solution. Aspirin (ASA) is one of such eminent drugs. Our study demonstrated that ASA may exert synergistic effect with the anti-Fas antibody on CSCs of colorectal cancer cell lines. We found that such compound treatment inhibited the pro-cancerous effect of anti-Fas stimulation and decreased spherogenicity, survival and CD133-positive cells’ count. Additionally, ASA with anti-Fas antibody may have a positive impact on dendritic cells’ functions. Our innovative study explored simultaneous usage of two biologically active compounds which haven’t been considered in such combination to assess their significance in colorectal cancer cell biology.

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Following the discovery of methods to generate large numbers of specific dendritic cells (DCs) ex vivo, the possibility of exploiting these cells in immunotherapeutic strategies will become a reality. It seems to be rationally to analyse the influence of the precursor source for further features and applications. For the needs of the given project DCs were derived from precursors derived from adult peripheral blood (APB) and umbilical cord blood (UCB). During some expansions of UCB CD34+ cells were separated giving non-adherent DCs (NA-DCs) or adherent DCs (A-DCs), whereas DCs derived from UCB precursors without separation gave rise to All-DCs. DC subpopulations were stimulated by lipopolysaccharides (LPS) or interferon- (IFN-), and afterwards the morphology, phenotype, and stimulatory properties were analysed. Our findings demonstrated that DCs generated from APB and UCB precursors were not equivalent and exhibited opposite features when expanded in comparable conditions. Additionally, all three subpopulations of UCB-derived DCs presented functional dissimilarities. Based on our results we concluded that the precursor source and the composition of media must be considered as crucial to the success of potential therapeutic application.

The therapy of colorectal cancer (CRC) patients is often unsuccessful because of the presence of cancer stem cells (CSCs) resistant to conventional approaches. Dendritic cells (DC)-based protocols are believed to effectively supplement CRC therapy. Our study was aimed to assess how the number and properties of CSCs isolated from tumor tissue of CRC patients will affect the biological characteristics of in vitro modified DCs. Similar procedures were conducted with the using of CRC HCT116 and HT29 cell lines. We found that the detailed configuration of CSC-like markers significantly influenced the maturation and activation of DCs after stimulation with cancer cells lysates or culture supernatants. This basic stimulatory effect was enhanced by LPS that is normally present in CRC CSCs niche. The increased number of CD29⁺ and CD44⁺ CSCs presented the opposite impact on treated DCs as showed by many significant correlations. The CD133⁺ CSCs seemed to impair the functions of DCs. The more CD133⁺ CSCs in tumor sample the lower number of activated DCs evidenced after stimulation. Moreover, our results showed superiority of the spherical culture model over the adherent one since spherical HCT116 and HT29 cells presented similar influence on DCs properties as CRC patients cancer cells. We concluded that the DCs features may depend directly on the properties of CSCs affected by progression status of tumor.

Spherical cultures (SCs) can be regarded in cancer research as a link between in vitro investigations on cancer lines and in vivo studies of tumor development. SCs are believed to mimic tumor architecture and to be enriched in cancer stem cell-like cells (CSC-like cells). In the present study we characterized colonospheres derived from colorectal cancer (CRC) cell lines, and we confirmed the ability of HCT116 and HT29 cell lines to form spheres within serum-free medium, however, the detailed analysis presented the major differences concerning their characteristics including morphology, phenotype, proliferative potential, distribution in the cell cycle phases and spherogenicity. Moreover, after we magnetically separated CD133+ and CD133- cells we could conduct the analogical analysis as we performed for the original cells. We observed that all cellular fractions unveiled sphere formation capacity, even when cultured in limited number of cells per well and only SCs originated from CD133+ fraction resembled morphologically the parental spheres. Both CD133+ and CD133- subsets derived from HCT116 line were more enriched in cells in G0/G1 phase of the cell cycle in comparison to their HT29 analogues. Additionally, proliferative potential also varied amongst all studied fractions. Surprisingly, 3-D invasion assay revealed that only HCT116-derived populations were able to migrate into extended regions of Matrigel Matrix confirming their higher aggressiveness. Our results provided comprehensive characterization of CRC cell lines culture in adherent and spherical forms and, what seems to be the most advantageous, the comparison of two distinct fractions after magnetic separation. As we found the specific features of cells presented line- and expansion mode-dependency, thus, such complete description might appear crucial before CRC lines would be involved into sophisticated assays, especially focused on potentially novel therapeutic agents targeting CSC-like cells.

Colorectal cancer (CRC) is the third most frequent malignancy and represents the fourth most common cause of cancer‑associated mortalities in the world. Despite many advances in the treatment of CRC, the 5‑year survival rate of patients with CRC remains unsatisfactory due to tumor recurrence and metastases. Recently, cancer stem cells (CSCs), have been suggested to be responsible for the initiation and relapse of the disease, and have been identified in CRC. Due to their basic biological features, which include self‑renewal and pluripotency, CSCs may be novel therapeutic targets for CRC and other cancer types. Conventional therapeutics only act on proliferating and mature cancer cells, while quiescent CSCs survive and often become resistant to chemotherapy. In this review, markers of CRC‑CSCs are evaluated and the recently introduced experimental therapies that specifically target these cells by inducing CSC proliferation, differentiation and sensitization to apoptotic signals via molecules including Dickkopf‑1, bone morphogenetic protein 4, Kindlin‑1, tankyrases, and p21‑activated kinase 1, are discussed. In addition, novel strategies aimed at inhibiting some crucial processes engaged in cancer progression regulated by the Wnt, transforming growth factor β and Notch signaling pathways (pyrvinium pamoate, silibinin, PRI‑724, P17, and P144 peptides) are also evaluated. Although the metabolic alterations in cancer were first described decades ago, it is only recently that the concept of targeting key regulatory molecules of cell metabolism, such as sirtuin 1 (miR‑34a) and AMPK (metformin), has emerged. In conclusion, the discovery of CSCs has resulted in the definition of novel therapeutic targets and the development of novel experimental therapies for CRC. However, further investigations are required in order to apply these novel drugs in human CRC.