Stem cell plasticity and dormancy in the development of cancer therapy resistance

Cancer treatment with either standard chemotherapy or targeted agents often results in the emergence of drug-refractory cell populations, ultimately leading to therapy failure. The biological features of drug resistant cells are largely overlapping with those of cancer stem cells and include heterogeneity, plasticity, self-renewal ability, and tumor-initiating capacity. Moreover, drug resistance is usually characterized by a suppression of proliferation that can manifest as quiescence, dormancy, senescence, or proliferative slowdown. Alterations in key cellular pathways such as autophagy, unfolded protein response or redox signaling, as well as metabolic adaptations also contribute to the establishment of drug resistance, thus representing attractive therapeutic targets. Moreover, a complex interplay of drug resistant cells with the micro/macroenvironment and with the immune system plays a key role in dictating and maintaining the resistant phenotype. Recent studies have challenged traditional views of cancer drug resistance providing innovative perspectives, establishing new connections between drug resistant cells and their environment and indicating unexpected therapeutic strategies. In this review we discuss recent advancements in understanding the mechanisms underlying drug resistance and we report novel targeting agents able to overcome the drug resistant status, with particular focus on strategies directed against dormant cells. Research on drug resistant cancer cells will take us one step forward toward the development of novel treatment approaches and the improvement of relapse-free survival in solid and hematological cancer patients

Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution

: The biological complexity of cancer represents a tremendous clinical challenge, resulting in the frequent failure of current treatment protocols. In the rapidly evolving scenario of a growing tumor, anticancer treatments impose a drastic perturbation not only to cancer cells but also to the tumor microenvironment, killing a portion of the cells and inducing a massive stress response in the survivors. Consequently, treatments can act as a double-edged sword by inducing a temporary response while laying the ground for therapy resistance and subsequent disease progression. Cancer cell dormancy (or quiescence) is a central theme in tumor evolution, being tightly linked to the tumor's ability to survive cytotoxic challenges, metastasize, and resist immune-mediated attack. Accordingly, quiescent cancer cells (QCCs) have been detected in virtually all the stages of tumor development. In recent years, an increasing number of studies have focused on the characterization of quiescent/therapy resistant cancer cells, unveiling QCCs core transcriptional programs, metabolic plasticity, and mechanisms of immune escape. At the same time, our partial understanding of tumor quiescence reflects the difficulty to identify stable QCCs biomarkers/therapeutic targets and to control cancer dormancy in clinical settings. This review focuses on recent discoveries in the interrelated fields of dormancy, stemness, and therapy resistance, discussing experimental evidences in the frame of a nonlinear dynamics approach, and exploring the possibility that tumor quiescence may represent not only a peril but also a potential therapeutic resource

Relationship between prolactin plasma levels and white matter volume in women with multiple sclerosis

BACKGROUND: The role of prolactin (PRL) on tissue injury and repair mechanisms in multiple sclerosis (MS) remains unclear. The aim of this work was to investigate the relationship between PRL plasma levels and brain damage as measured by magnetic resonance imaging (MRI). METHODS: We employed a chemiluminescence immunoassay for measuring plasma levels of PRL. We used a 1.5 T scanner to acquire images and Jim 4.0 and SIENAX software to analyse them. RESULTS: We included 106 women with relapsing remitting (RR) MS and stable disease in the last two months. There was no difference in PRL plasma levels between patients with and without gadolinium enhancement on MRI. PRL plasma levels correlated with white matter volume (WMV) (rho = 0.284, p = 0.014) but not with grey matter volume (GMV). Moreover, PRL levels predicted changes in WMV (Beta: 984, p = 0.034). CONCLUSIONS: Our data of a positive association between PRL serum levels and WMV support the role of PRL in promoting myelin repair as documented in animal models of demyelination. The lack of an increase of PRL in the presence of gadolinium enhancement, contrasts with the view considering this hormone as an immune-stimulating and detrimental factor in the inflammatory process associated with MS

Oral contraceptives combined with interferon β in multiple sclerosis

Objective: To test the effect of oral contraceptives (OCs) in combination with interferon b (IFN-b) on disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: One hundred fifty women with RRMS were randomized in a 1:1:1 ratio to receive IFNb-1a subcutaneously (SC) only (group 1), IFN-b-1a SC plus ethinylstradiol 20 mg and desogestrel 150 mg (group 2), or IFN-b-1a SC plus ethinylestradiol 40 mg and desogestrel 125 mg (group 3). The primary endpoint was the cumulative number of combined unique active (CUA) lesions on brain MRI at week 96. Secondary endpoints included MRI and clinical and safety measures. Results: The estimated number of cumulative CUA lesions at week 96 was 0.98 (95% confidence interval [CI] 0.81–1.14) in group 1, 0.84 (95% CI 0.66–1.02) in group 2, and 0.72 (95% CI 0.53–0.91) in group 3, with a decrease of 14.1% (p 5 0.24) and 26.5% (p 5 0.04) when comparing group 1 with groups 2 and 3, respectively. The number of patients with no gadoliniumenhancing lesions was greater in group 3 than in group 1 (p 5 0.03). No significant differences were detected in other secondary endpoints. IFN-b or OC discontinuations were equally distributed across groups. Conclusions: Our results translate the observations derived from experimental models to patients, supporting the anti-inflammatory effects of OCs with high-dose estrogens, and suggest possible directions for future research

Lung Cancer Organoids. The Rough Path to Personalized Medicine

Lung cancer is the leading cause of cancer death worldwide. Despite significant advances in research and therapy, a dismal 5-year survival rate of only 10–20% urges the development of reliable preclinical models and effective therapeutic tools. Lung cancer is characterized by a high degree of heterogeneity in its histology, a genomic landscape, and response to therapies that has been traditionally difficult to reproduce in preclinical models. However, the advent of three-dimensional culture technologies has opened new perspectives to recapitulate in vitro individualized tumor features and to anticipate treatment efficacy. The generation of lung cancer organoids (LCOs) has encountered greater challenges as compared to organoids derived from other tumors. In the last two years, many efforts have been dedicated to optimizing LCO-based platforms, resulting in improved rates of LCO production, purity, culture timing, and long-term expansion. However, due to the complexity of lung cancer, further advances are required in order to meet clinical needs. Here, we discuss the evolution of LCO technology and the use of LCOs in basic and translational lung cancer research. Although the field of LCOs is still in its infancy, its prospective development will likely lead to new strategies for drug testing and biomarker identification, thus allowing a more personalised therapeutic approach for lung cancer patients

Safe use of human anatomical preparations in frontal and interactive teaching

In the institute of Human Anatomy of Pavia, the use of cadaver dissection is not economically feasible. In order to improve students’ preparation related to topography of the central nervous system, we decided to use formalin-fixed brains and cranial sections belonging to the collection of cadaveric specimens. These specimens, preserved in formalin, however cannot be manipulated as such by the students because formalin can cause headaches, burning sensation in the throat, difficult breathing and can trigger or aggravate asthma symptoms [1, 2]. Furthermore, formalin is known to be a human carcinogen [3]. In order to minimize toxic effects, whole brains were extensively washed in running water and then sliced according to different reference planes using a “home-made” device enabling cuts according to parallel planes. Finally, the resulting sections were inserted into transparent plastic envelopes, immerged in a solution composed by 0.5% agar and 1% sodium azide as preservative. Medical students can now use these human brain sections to test their own ability to recognize nervous system structures. This strategy optimize specimen’s choice and focalize student’s attention on peculiar, selected human samples in full compliance with current security laws

Salinomycin potentiates the cytotoxic effects of TRAIL on glioblastoma cell lines

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to exhibit therapeutic activity in cancer. However, many tumors remain resistant to treatment with TRAIL. Therefore, small molecules that potentiate the cytotoxic effects of TRAIL could be used for combinatorial therapy. Here we found that the ionophore antibiotic salinomycin acts in synergism with TRAIL, enhancing TRAIL-induced apoptosis in glioma cells. Treatment with low doses of salinomycin in combination with TRAIL augmented the activation of caspase-3 and increased TRAIL-R2 cell surface expression. TRAIL-R2 upmodulation was required for mediating the stimulatory effect of salinomycin on TRAIL-mediated apoptosis, since it was abrogated by siRNA-mediated TRAIL-R2 knockdown. Salinomycin in synergism with TRAIL exerts a marked anti-tumor effect in nude mice xenografted with human glioblastoma cells. Our results suggest that the combination of TRAIL and salinomycin may be a useful tool to overcome TRAIL resistance in glioma cells and may represent a potential drug for treatment of these tumors. Importantly, salinomycin+TRAIL were able to induce cell death of well-defined glioblastoma stem-like lines

Vineyard establishment under exacerbated summer stress: effects of mycorrhization on rootstock agronomical parameters, leaf element composition and root-associated bacterial microbiota

Aims Climate change imposes adaptation of viticulture in risk areas, such as the Mediterranean. Mycorrhization is a valid tool to reduce the impact of the expected temperature/drought increase. Aim of this work was to test the effects of mycorrhization on grapevine vegetative growth, element composition of soil/leaves, and microbiota of bulk soil/rhizosphere/endorhiza, in the field, under exacerbated summer stress conditions obtained by planting the rootstocks in June. Methods 118 rooted cuttings of 1103-Paulsen (Vitis berlandieri × Vitis rupestris) were planted in Salento (Apulia, Southern Italy); about half of them were mycorrhized. Leaf Area Index, shoot growth and survival rate were monitored across two growing seasons. Leaf/shoot weight, chemical analysis of 25 elements, and 16S rRNA gene metabarcoding of bulk soil/rhizosphere/endorhiza were performed on subsamples. Results Mycorrhized plants showed significantly higher survival rate and growth, and accumulated significantly higher amounts of 18 elements. 27 endorhizal OTUs (representing ~20% of total sequences) were differently distributed (20 OTUs more abundant in mycorrhized plants); in the rhizosphere, instead, 12 OTUs (~2.5% of total sequences) were differently distributed. A few Actinobacterial OTUs were enriched by mycorrhization in the root endosphere; the same OTUs were the most correlated with the chemical elements, suggesting a role in element dynamics. These OTUs were not hub taxa of the co-occurrence network. Conclusions This work shed light onto the interactions between mycorrhiza and microbiome, in the context of plant element dynamics, which is useful to identify potential target candidates for biotechnological applications, thus moving towards a more sustainable, ecosystem-based viticulture