Colorectal cancer is a major public health concern, with increasing incidence and mortality rates worldwide. Environmental factors, including exposure to toxic metals, such as lead, chromium, cadmium, aluminium, copper, arsenic and mercury, have been suggested to play a significant role in the development and progression of this neoplasia. In particular, the bioaccumulation of toxic metals can play a significant role in colorectal cancer by regulating biological phenomenon associated to both cancer occurrence and progression, such as cell death and proliferation. Also, frequently these metals can induce DNA mutations in well-known oncogenes. This review provides a critical analysis of the current evidence, highlighting the need for further research to fully grasp the complex interplay between toxic metal bioaccumulation and colorectal cancer. Understanding the contribution of toxic metals to colorectal cancer occurrence and progression is essential for the development of targeted preventive strategies and social interventions, with the ultimate goal of reducing the burden of this disease.

We investigated the presence of aluminium (Al) in human colon cancer samples and its potential association with biological processes involved in cancer progression, such as epithelial to mesenchymal transition (EMT) and cell death. 25 consecutive colon samples were collected from patients undergoing colonic resection. Both neoplastic and normal mucosa were collected from each patient and subjected to histological, ultrastructural and immunohistochemical analyses. Moreover, colon samples from two Al-positive patients underwent multi-omic analyses, including whole genome sequencing and RNA sequencing (RNAseq). Morin staining, used to identify in situ aluminium bioaccumulation, showed the presence of Al in tumor areas of 24 % of patients. Transmission electron microscopy and energy-dispersive X-ray microanalysis confirmed the presence of Al specifically in intracytoplasmic electrondense nanodeposits adjacent to mitochondria of colon cancer cells. Immunohistochemical analyses for vimentin and nuclear β-catenin were performed to highlight the occurrence of the EMT phenomenon in association to Al bioaccumulation. Al-positive samples showed a significant increase in both the number of vimentin-positive and nuclear β-catenin-positive cancer cells compared to Al-negative samples. Moreover, Al-positive samples exhibited a significant decrease in the number of apoptotic cells, as well as the expression of the anti-apoptotic molecule BCL-2. Multi-omic analyses revealed a higher tumor mutational burden (TMB) in Al-positive colon cancers (n = 2) compared to a control cohort (n = 100). Additionally, somatic mutations in genes associated with EMT (GATA3) and apoptosis (TP53) were observed in Al-positive colon cancers. In conclusion, this study provides the first evidence of Al bioaccumulation in colon cancer and its potential role in modulating molecular pathways involved in cancer progression, such as EMT and apoptosis. Understanding the molecular mechanisms underlying Al toxicity might contribute to improve strategies for prevention, early detection, and targeted therapies for the management of colon cancer patients.

BACKGROUND: Dyslipidemia plays a critical role in carotid plaque instability and related cerebrovascular events. Reduction of low-density lipoprotein cholesterol (LDL-C) levels decreases ischemic stroke risk; however, a residual cardiovascular risk persists. Starting from this evidence, this study evaluated the impact of dyslipidemia on carotid plaque instability while also considering age and sex. METHODS: In this observational study, a total of 354 carotid plaques from symptomatic and asymptomatic patients undergoing endarterectomy were analyzed histologically. Dyslipidemic profiles, including high LDL-C, remnant cholesterol, triglycerides, and low high-density lipoprotein cholesterol, were assessed alongside other risk factors. Logistic regression identified independent predictors of unstable plaques, and subgroup analyses evaluated the influence of age (<70, ≥70 years) and sex. RESULTS: Unstable plaques were observed in 45.2% of cases. High LDL-C emerged as the strongest independent risk factor for plaque instability. The combination of high LDL-C with elevated remnant cholesterol or triglycerides significantly increased the risk of plaque destabilization. Age and sex influenced the risk associated with dyslipidemic profiles, with women who had elevated LDL-C combined with high-remnant cholesterol or triglycerides showing a substantially higher risk of carotid plaque instability compared with men. Furthermore, individuals <70 years of age exhibited a greater risk of plaque instability compared with older patients, highlighting the critical role of these nonmodifiable factors. CONCLUSIONS: The data reported here highlight the importance of a personalized medicine approach to lipid management, addressing not only LDL-C but also remnant cholesterol and triglycerides. Tailored interventions targeting specific dyslipidemic profiles could more effectively reduce the risk of carotid plaque rupture and cerebrovascular events, particularly in women and patients aged <70 years.

Cholangiocarcinoma is a highly aggressive cancer arising from the bile ducts. The limited effectiveness of conventional therapies has prompted the search for new approaches to target this disease. Recent evidence suggests that distinct programmed cell death mechanisms, namely, apoptosis, ferroptosis, pyroptosis and necroptosis, play a critical role in the development and progression of cholangiocarcinoma. This review aims to summarize the current knowledge on the role of programmed cell death in cholangiocarcinoma and its potential implications for the development of novel therapies. Several studies have shown that the dysregulation of apoptotic signaling pathways contributes to cholangiocarcinoma tumorigenesis and resistance to treatment. Similarly, ferroptosis, pyroptosis and necroptosis, which are pro-inflammatory forms of cell death, have been implicated in promoting immune cell recruitment and activation, thus enhancing the antitumor immune response. Moreover, recent studies have suggested that targeting cell death pathways could sensitize cholangiocarcinoma cells to chemotherapy and immunotherapy. In conclusion, programmed cell death represents a relevant molecular mechanism of pathogenesis in cholangiocarcinoma, and further research is needed to fully elucidate the underlying details and possibly identify therapeutic strategies.

Breast cancer is the most common cancer and the second leading cause of cancer-related death in women. In advanced stages of the disease, breast cancer can spread and metastasize to the bone, contributing to malignant progression. The roles of tissue stiffness and remodeling of the tumor microenvironment are relevant in influencing cancer progression and invasiveness, but they are still poorly understood. In this study, we aimed to investigate the effect of bone tissue stiffness on breast cancer cell behavior, using 3D cell–biomaterial systems to model the in vivo conditions. For this purpose, we developed a 3D-printable cell array, which is a tunable and reproducible platform on small scale, where each compartment could mimic the physiological cancer environment with a shape and rigidity close to bone tissue. In this system, we observed that in the highly metastatic breast cancer line MDA-MB-231, embedded in PEG–silk fibroin (PSF) hydrogel spheres in the array’s cavities, increasing stiffness promotes trans-differentiation into osteoblast-like cells and the production of breast microcalcifications. Moreover, we also tested this 3D model as a platform to evaluate the cell response to the therapy, in particular, investigating the drug sensitivity of the cancer cells to chemotherapeutics, observing a decrease in drug resistance over time in the array.

The growing incidence of breast cancer over time suggests that environmental factors might contribute to the underlying causes of the disease. Mercury, a toxic metal classified as a Substance of Very High Concern, accumulates in the body through contaminated food, air, water, and soil, raising concerns about its role in tumor biology. The main aim of this study was to identify the possible associations between in situ mercury bioaccumulation and the molecular features of breast cancer. To achieve this, a total of 26 breast cancer cases were analyzed using an integrated approach that combined DNA and RNA sequencing, histological analysis, and inductively coupled plasma mass spectrometry (ICP-MS) to assess mercury bioaccumulation. Mercury was detected in 72% of the cases. A significant positive correlation was found between mercury bioaccumulation and CXCR4 expression in breast cancer tissues. Bioinformatic analysis further revealed that CXCR4 expression was significantly higher in metastatic tissues compared to primary tumors. These findings suggest that mercury accumulation may influence tumor biology through the CXCR4-CXCL12 signaling pathway, highlighting a potential mechanism by which mercury contributes to breast cancer progression.