Latest articles in this journal
Cancers, Volume 15; https://doi.org/10.3390/cancers15041108
Epithelial-to-mesenchymal transition (EMT) is known to be important in regulating the behaviour of cancer cells enabling them to acquire stem cell characteristics or by enhancing the stem cell characteristics of cancer stem cells, resulting in these cells becoming more migratory and invasive. EMT can be driven by a number of mechanisms, including the TGF-β1 signalling pathway and/or by hypoxia. However, these drivers of EMT differ in their actions in regulating side population (SP) cell behaviour, even within SPs isolated from the same tissue. In this study we examined CoCl2 exposure and TGF-β driven EMT on SP cells of the MDA-MB-231 and MCF7 breast cancer cell lines. Both TGF-β1 and CoCl2 treatment led to the depletion of MDA-MB-231 SP. Whilst TGF-β1 treatment significantly reduced the MCF7 SP cells, CoCl2 exposure led to a significant increase. Single cell analysis revealed that CoCl2 exposure of MCF7 SP leads to increased expression of ABCG2 and HES1, both associated with multi-drug resistance. We also examined the mammosphere forming efficiency in response to CoCl2 exposure in these cell lines, and saw the same effect as seen with the SP cells. We suggest that these contrasting effects are due to ERα expression and the inversely correlated expression of TGFB-RII, which is almost absent in the MCF7 cells. Understanding the EMT-mediated mechanisms of the regulation of SP cells could enable the identification of new therapeutic targets in breast cancer.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041109
CD20 monoclonal antibodies (mAbs) eliminate B cells in several clinical contexts. At least two of these Abs, obinutuzumab (OBI) and rituximab (RTX), induce quick elimination of targets and put cancer patients at risk of tumor lysis syndrome (TLS) within 12–24 h of the first dose. The mechanisms of killing can require the recruiting of effector mechanisms from the patient’s immune system, but they can induce direct killing as well. This can be more rapid than recruiting cellular effectors and/or complement. We showed here that OBI and RTX induce quick (<1 h) and high (up to 60% for OBI) killing of two different B cell lines. This was unveiled by using two different techniques that circumvent cell centrifugation steps: a Muse® Cell Analyzer-based approach and a direct examination of the cells’ physical properties by using forward scatter (FS) area and side scatter (SS) area by flow cytometry. These results excluded the presence of aggregates and were also confirmed by developing a normalized survival ratio based on the co-incubation of RTX- and OBI-sensitive cells with MOLM-13, an insensitive cell line. Finally, this normalized survival ratio protocol confirmed the RTX- and OBI-direct killing on primary tumor B cells from B cell chronic lymphocytic leukemia (B-CLL) and Non-Hodgkin’s lymphoma (NHL) patients. Moreover, we unveiled that direct killing is higher than previously expected and absent in patients’ samples at relapse. We also observed that these mAbs, prior to increasing intracellular calcium levels, decrease calcium entry, although manipulating calcium levels did not affect their cytotoxicity. Altogether, our results show that direct killing is a major mechanism to induce cell death by RTX and OBI mAbs.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041107
Colorectal cancer (CRC) is a leading public health concern due to its incidence and high mortality rates, highlighting the requirement of an early diagnosis. Evaluation of circulating extracellular vesicles (EVs) might constitute a noninvasive and reliable approach for CRC detection and for patient follow-up because EVs display the molecular features of the cells they originate. EVs are released by almost all cell types and are mainly categorized as exosomes originating from exocytosis of intraluminal vesicles from multivesicular bodies, ectosomes resulting from outward budding of the plasma membrane and apoptotic bodies’ ensuing cell shrinkage. These vesicles play a critical role in intercellular communications during physiological and pathological processes. They facilitate CRC progression and premetastatic niche formation, and they enable transfer of chemotherapy resistance to sensitive cells through the local or remote delivery of their lipid, nucleic acid and protein content. On another note, their stability in the bloodstream, their permeation in tissues and their sheltering of packaged material make engineered EVs suitable vectors for efficient delivery of tracers and therapeutic agents for tumor imaging or treatment. Here, we focus on the physiopathological role of EVs in CRCs, their value in the diagnosis and prognosis and ongoing investigations into therapeutic approaches.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041106
The use of immunotherapy in the treatment of advanced and high-risk melanoma has led to a striking improvement in outcomes. Although the incidence of melanoma has continued to rise, median survival has improved from approximately 6 months to nearly 6 years for patients with advanced inoperable stage IV disease. Recent understanding of the tumor microenvironment and its interplay with the immune system has led to the explosive development of novel immunotherapy treatments. Since the approval of the therapeutic cytokines interleukin-2 and interferon alfa-2 in the 1990s, the development of novel immune checkpoint inhibitors (ICIs), oncolytic virus therapy, and modulators of the tumor microenvironment have given way to a new era in melanoma treatment. Monoclonal antibodies directed at programmed cell death protein 1 receptor (PD-1) and its ligand (PDL-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) have provided robust activation of the adaptive immune system, restoring immune surveillance leading to host tumor recognition and destruction. Multiple other immunomodulatory therapeutics are under investigation to overcome resistance to ICI therapy, including the toll-like receptor-9 (TLR-9) and 7/8 (TLR-7/8) agonists, stimulator of interferon genes (STING) agonists, and fecal microbiota transplantation. In this review, we focus on the recent advances in immunotherapy for the treatment of melanoma and provide an update on novel therapies currently under investigation.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041104
Colorectal cancer (CRC) is a molecular and clinically heterogeneous disease. In 2015, the Colorectal Cancer Subtyping Consortium classified CRC into four consensus molecular subtypes (CMS), but these CMS have had little impact on clinical practice. The purpose of this study is to deepen the molecular characterization of CRC. A novel approach, based on probabilistic graphical models (PGM) and sparse k-means–consensus cluster layer analyses, was applied in order to functionally characterize CRC tumors. First, PGM was used to functionally characterize CRC, and then sparse k-means–consensus cluster was used to explore layers of biological information and establish classifications. To this aim, gene expression and clinical data of 805 CRC samples from three databases were analyzed. Three different layers based on biological features were identified: adhesion, immune, and molecular. The adhesion layer divided patients into high and low adhesion groups, with prognostic value. The immune layer divided patients into immune-high and immune-low groups, according to the expression of immune-related genes. The molecular layer established four molecular groups related to stem cells, metabolism, the Wnt signaling pathway, and extracellular functions. Immune-high patients, with higher expression of immune-related genes and genes involved in the viral mimicry response, may benefit from immunotherapy and viral mimicry-related therapies. Additionally, several possible therapeutic targets have been identified in each molecular group. Therefore, this improved CRC classification could be useful in searching for new therapeutic targets and specific therapeutic strategies in CRC disease.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041103
Aim: Healthcare administrative databases represent a valuable source for real-life data analysis. The primary aim of this study is to compare effectiveness and cost profile in non-small-cell lung cancer (NSCLC) patients harboring synchronous brain metastases (BMs) who received non-chemo first-line systemic therapy with or without advanced radiotherapy (aRT). Methods: Diagnostic ICD-9-CM codes were used for identifying all patients with a new diagnosis of lung cancer between 2012 and 2019. Among these, patients who had started a first-line systemic treatment with either TKIs or pembrolizumab, alone or in combination with intensity-modulated or stereotactic RT, were selected. Clinical outcomes investigated included overall survival (OS), progression-free survival (PFS), and time-to-treatment failure (TTF). The cost outcome was defined as the average per capita cumulative healthcare direct costs of the treatment, including all inpatient and outpatient costs. Results: The final cohort included 177 patients, of whom 58 were treated with systemic treatment plus aRT (STRT) and 119 with systemic treatment alone. The addition of aRT to systemic treatment was associated with a significantly better OS (p = 0.020) and PFS (p = 0.041) than systemic therapy alone. The ICER (incremental cost-effectiveness ratio) value indicated an average cost of €3792 for each month of survival after STRT treatment and confirmed clinical effectiveness but higher healthcare costs. Conclusions: This real-world study suggests that upfront aRT for NCLSC patients with synchronous BMs represents a valid treatment strategy, boosting the efficacy of novel and emerging drug classes with sustainable costs for the health service. Translational relevance: The present real-world study reports that the use of upfront advanced radiotherapyaRT and new-generation systemic agents, such as TKIs and pembrolizumab, may have higher oncological control and an improved cost-effectiveness profile than the use of new-generation systemic agents alone in NCLSC patients with synchronous brain metastases. Acquired evidence can also be used to inform policymakers that adding advanced radiotherapy results is a sustainable cost for the health service. Since approximately 50% of patients do not meet RCT inclusion criteria, a significant proportion of them is receiving treatment that is not evidence-informed; therefore, these results warrant further studies to identify the best radiotherapy timing and possible dose escalation approaches to improving treatment efficacy in patient subgroups not typically represented in randomized controlled trials.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041102
Inflammatory Bowel Disease (IBD) is a category of autoimmune diseases that targets the destruction of the gastrointestinal system and includes both Crohn’s Disease and Ulcerative Colitis (UC). Patients with IBD are at a higher risk of developing colorectal cancer (CRC) throughout their lives due to chronically increased inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are potential chemopreventative agents that can inhibit the development of CRC in persons without IBD. However, the use of NSAIDs for CRC chemoprevention in IBD patients is further complicated by NSAIDs’ induction of damage to the bowel mucosal layer and ulcer formation. There has been a push in new research on chemopreventative properties of certain NSAIDs for IBD. The purpose of this umbrella review is to investigate the potential of low-dose NSAID compounds as chemopreventative agents for patients with IBD. This paper will also suggest future areas of research in the prevention of CRC for patients with IBD.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041105
This study aims to investigate the association of pre-treatment multi-phasic MR-based radiomics and dosimetric features with treatment response to a novel sequential trans-arterial chemoembolization (TACE) plus stereotactic body radiotherapy (SBRT) plus immunotherapy regimen in unresectable Hepatocellular Carcinoma (HCC) sub-population. Twenty-six patients with unresectable HCC were retrospectively analyzed. Radiomic features were extracted from 42 lesions on arterial phase (AP) and portal-venous phase (PVP) MR images. Delta-phase (DeltaP) radiomic features were calculated as AP-to-PVP ratio. Dosimetric data of the tumor was extracted from dose-volume-histograms. A two-sided independent Mann–Whitney U test was used to assess the clinical association of each feature, and the classification performance of each significant independent feature was assessed using logistic regression. For the 3-month timepoint, four DeltaP-derived radiomics that characterize the temporal change in intratumoral randomness and uniformity were the only contributors to the treatment response association (p-value = 0.038–0.063, AUC = 0.690–0.766). For the 6-month timepoint, DeltaP-derived radiomic features (n = 4) maintained strong clinical associations with the treatment response (p-value = 0.047–0.070, AUC = 0.699–0.788), additional AP-derived radiomic features (n = 4) that reflect baseline tumoral arterial-enhanced signal pattern and tumor morphology (n = 1) that denotes initial tumor burden were shown to have strong associations with treatment response (p-value = 0.028–0.074, AUC = 0.719–0.773). This pilot study successfully demonstrated associations of pre-treatment multi-phasic MR-based radiomics with tumor response to the novel treatment regimen.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041101
Although conversion surgery has increasingly been performed for initially unresectable advanced pancreatic ductal adenocarcinoma (PDAC), the rate of conversion, including that for patients who do not undergo resection, remains unclear. Patients with PDAC who were treated between January 2013 and December 2018 were classified into three groups: resectable (R), borderline resectable (BR), and unresectable (UR). We analyzed patient outcomes, including the rate of surgical resection and survival, in each of these groups. In total, 211 patients (R, 118; BR, 22; UR, 81) were selected. Among them, 117 (99%), 18 (82%), and 15 (19%) patients in the R, BR, and UR groups, respectively, underwent surgical resection. R0 resection rates were 88, 78, and 67%, whereas median overall survival (OS) from treatment initiation were 31, 18, and 11 months (p < 0.0001) in the R, BR, and UR groups, respectively. In patients who underwent surgical resection, relapse-free survival (RFS) and OS were similar among the three groups (R vs. BR vs. UR; median RFS (months), 17 vs. 13 vs. 11, p = 0.249; median OS (months), 31 vs. 26 vs. 32, p = 0.742). Lymph node metastases and incomplete adjuvant chemotherapy were identified as independent prognostic factors for OS. Although the surgical resection rate was low, particularly in the BR and UR groups, the prognosis of patients who underwent surgical resection was similar irrespective of the initial resectability status.
Cancers, Volume 15; https://doi.org/10.3390/cancers15041100
Objective: Psychological distress is considered a factor for cancer development. However, the impact of mood disorders (depression and bipolar) on the development of cervical cancer remains uncertain. We conducted a nationwide population-based retrospective cohort study to investigate the association between mood disorders and the subsequent risk of developing cervical cancer. Methods: A total of 138,130 participants’ profiles between 2000 and 2012 were extracted from the National Health Insurance Research Database and subdivided into a mood-disorder cohort (27,626 participants) and a non-mood-disorder cohort (110,504 participants). Cohorts were propensity-matched for a 1:4 ratio according to age and index year. The Cox proportional hazards regression model was utilized for assessing cervical cancer risk between cohorts. Results: Kaplan–Meier analysis revealed that the mood-disorder cohort had a higher cumulative incidence of cervical cancer. The mood-disorder cohort was also associated with an increased risk of cervical cancer after adjustments for potential confounders. Subgroup analysis revealed a negative impact of mood disorders on cervical cancer, especially in the 30–50 years and white-collar groups. Conclusions: Our findings demonstrated that mood disorders were associated with an increased risk of cervical cancer development, which provide helpful information for clinical strategies to reduce the incidence of cervical cancer in this vulnerable population.