This study aimed to elucidate the clinical outcomes of patients with pathologic T3 (pT3) and pathologic T4 (pT4) tumors who underwent radical resection with multivisceral resection (MVR) and to assess the prognostic significance of MVR in locally advanced colorectal cancers (CRCs) in pT3 and pT4 tumors.

This multicenter retrospective analysis evaluated the characteristics, clinicopathologic stages, perioperative factors, and clinical outcomes of patients who underwent primary colorectal resection. Patients were divided into 4 groups: those with a pT3 tumor who did not undergo MVR (pT3 - MVR; n = 1108), those with a pT3 tumor who underwent MVR (pT3 + MVR; n = 56), those with a pT4 tumor who did not undergo MVR (pT4 - MVR; n = 306), and those with a pT4 tumor who did underwent MVR (pT4 + MVR; n = 123). Univariate and multivariate regression analyses were performed to identify risk factors for recurrence.

The pT3 + MVR group exhibited a higher 5-year recurrence rate than the pT3 - MVR group, with recurrence rates similar to those of the pT4 - MVR or pT4 + MVR groups (pT3 - MVR, 17.4%; pT3 + MVR, 31.6%; pT4 - MVR, 33.4%; pT4 + MVR, 35.1%). Multivariate analysis identified MVR as an independent risk factor for recurrence, particularly peritoneal dissemination, in pT3 tumors, whereas MVR had less effect on recurrence in pT4 tumors.

pT3 tumors requiring MVR had a higher recurrence rate than pT4 tumors. The surgeon's clinical assessment of potential T4 tumors requiring MVR at the time of surgery was an important prognostic indicator in advanced CRC.

Obesity is an important risk factor for incidence and death for many types of cancer. Vitamin D reduces risk of incidence and death for many types of cancer. This review outlines the mechanisms by which obesity increases risk of cancer, how vitamin D reduces risk of cancer, and the extent to which vitamin D counters the effects of obesity in cancer. Vitamin D is a partial ally against some of obesity's pro-carcinogenic effects, notably by reducing inflammation and regulating sex hormone receptors, leptin resistance, cellular energy metabolism, the microbiome, and hypoxia. However, it can act stronger in against the renin-angiotensin system, insulin resistance, and oxidative stress in cancer. Additionally, excess fat tissue sequesters vitamin D and, along with its dilution in increased body volume, further reduces its bioavailability and serum concentration, limiting its protective effects against cancer. In conclusion, while vitamin D cannot reverse obesity, it plays a significant role in mitigating its pro-carcinogenic effects by targeting several mechanisms.

Higher concentration of insulin-like growth factor-1 (IGF-1) increases postmenopausal breast cancer risk, but evidence for insulin and c-peptide is limited. Furthermore, not all studies have accounted for potential confounding by biomarkers from other biological pathways, and not all were restricted to estrogen receptor (ER)-positive breast cancer.

This was a case-cohort study of 1,223 postmenopausal women (347 with ER-positive breast cancer) from the Melbourne Collaborative Cohort Study. We measured insulin, c-peptide, IGF-1, insulin-like growth factor binding protein-3, and biomarkers of inflammatory and sex-steroid hormone pathways. Poisson regression with a robust variance estimator was used to estimate risk ratios (RR) and 95% confidence intervals (95% CI) for ER-positive breast cancer per doubling plasma concentration and for quartiles, without and with adjustment for other, potentially confounding biomarkers.

ER-positive breast cancer risk was not associated with doubling of insulin (RR = 0.97, 95% CI, 0.82-1.14) or c-peptide (RR = 1.01, 95% CI, 0.80-1.26). Risk seemed to decrease with doubling IGF-1 (RR = 0.80, 95% CI, 0.62-1.03) and insulin-like growth factor binding protein-3 (RR = 0.62, 95% CI, 0.41-0.90). RRs were not meaningfully different when exposures were modeled as quartiles. RRs were less than unity but imprecise after adjustment for inflammatory and sex-steroid hormone biomarkers.

Circulating insulin, c-peptide, and IGF-1 were not positively associated with risk of ER-positive breast cancer in this case-cohort analysis of postmenopausal women.

Associations between insulin and c-peptide and risk of ER-positive breast cancer in postmenopausal women are likely to be weak.

Many patients with metastatic breast cancer can live relatively long lives but are challenged by treatment- and cancer-related side effects such as weight gain, physical deconditioning, and reduced quality of life, possibly affecting survival. In particular, endocrine treatments are associated with an increased risk of weight gain and adverse metabolic effects. There is a need for interventions to prevent side effects among patients with disseminated breast cancer. Exercise is found to be effective in improving quality of life, metabolic health, and body composition in the curative setting, yet evidence in the metastatic setting is sparse. The aim of this study is to assess feasibility of a 12-week exercise intervention for metastatic breast cancer patients with overweight receiving endocrine therapy and to explore potential effects on metabolic health, body composition, physical performance, obesity-related biomarkers, and patient-reported outcomes.

The FEMA study is a randomized controlled feasibility trial in which 21 endocrine-treated patients with metastatic breast cancer and overweight will be randomly assigned in a 2:1 ratio to either a 12-week training program with three weekly training sessions (intervention), or usual care (control), which includes standard clinical follow-up and supportive care without structured exercise. Feasibility will be assessed based on recruitment rate, adherence, retention, and acceptability, employing both quantitative and qualitative approaches for data collection. Participants' experiences will be explored by interviews and analyzed based on content analysis. Data are collected from blood samples, bioelectrical impedance analysis, physical performance tests, blood pressure measurements, and validated questionnaires on health-related quality of life, self-efficacy for coping with cancer, and sleep quality for explorative analyses.

The planned study will allow us to determine whether this 12-week exercise intervention is feasible in endocrine-treated metastatic breast cancer patients with overweight and explore potential effects on metabolic health, body composition, physical performance, obesity-related biomarkers, and patient-reported outcomes. Information from feasibility outcomes will inform the design of a future definitive randomized controlled trial.

Retrospectively registered on March 6, 2024, at ClinicalTrials.gov (NCT06343987).

Adipose tissue is an immunologically active organ that controls host physiology, partly through the release of mediators termed adipokines. In obesity, adipocytes and infiltrating leukocytes produce adipokines, which include the hormones adiponectin and leptin and cytokines such as tumour necrosis factor and IL-1β. These adipokines orchestrate immune responses that are collectively referred to as metabolic inflammation. Consequently, metabolic inflammation characterizes metabolic disorders and promotes distinct disease aspects, such as insulin resistance, metabolic dysfunction-associated liver disease and cardiovascular complications. In this unifying concept, adipokines participate in the immunological cross-talk that occurs between metabolically active organs in metabolic diseases, highlighting the fundamental role of adipokines in obesity and their potential for therapeutic intervention. Here, we summarize how adipokines shape metabolic inflammation in mice and humans, focusing on their contribution to metabolic disorders in the setting of obesity and discussing their value as therapeutic targets.

Ultra-processed foods (UPFs) are becoming more and more important in daily diets around the world; in some cases, they can account for as much as 60% of daily energy intake. Epidemiological evidence suggests that this shift toward high levels of food processing may be partially responsible for the global obesity epidemic and the rise in the prevalence of chronic diseases.

Few prospective studies have examined the relationship between UPF consumption and cancer outcomes. According to currently available information, UPFs may increase the risk of cancer due to their obesogenic properties and exposure to substances that can cause cancer, such as certain food additives and pollution from product processing. The complex relationship between obesity and cancer involves factors such as immune dysregulation, altered adipokine and sex hormone levels, abnormal fatty acid metabolism, extracellular matrix remodeling, and chronic inflammation. Addressing cancer risk associated with UPF consumption could involve a multifaceted approach, including consumer behavior modification programs and robust public health regulations aimed at enhancing food environments. Improved knowledge of the potential dual negative impacts of UPFs on the environment and cancer risk is one of the priority areas we identify for future research and policy implications. Various approaches could be used to prevent cancers associated with UPF consumption, such as consumer behavior change programs and stricter public health regulations needed to improve the food environment. This review examines for the first time the potential role of UPFs in cancer risk associated with obesity, exploring underlying biological mechanisms and identifying key areas for future research and policy action, including the dual environmental and health impact of UPFs.

General obesity commonly represented by body mass index (BMI) is an established risk factor for colorectal cancer (CRC). However, it is unclear to what extent this association is accounted for by central obesity. We aimed to evaluate the associations between BMI, waist-to-hip ratio (WHR), and waist circumference (WC) with CRC risk and to investigate if and to what extent these associations are independent from each other.

Data from more than 500,000 male and female participants aged 40-69, recruited in the UK Biobank study between 2006 and 2010, were analyzed. Multivariable Cox proportional hazards models were fitted and hazard ratios (HR) and their 95% confidence intervals (CI) were calculated.

During a median follow-up of 12.5 years, of 460,784 participants, 5,977 developed CRC. Multivariable adjusted HRs (95% CIs) per standard deviation increase of BMI, WHR, and WC were 1.10 (1.07-1.13), 1.18 (1.14-1.22), and 1.14 (1.11-1.18), respectively. After mutual adjustment, the association with CRC was substantially attenuated for BMI (1.04 (1.01-1.07)), and remained substantially stronger for WHR (1.15 (1.11-1.20)). Furthermore, WHR showed strong, statistically significant associations with CRC risk within all BMI categories, whereas associations of BMI with CRC risk were weak and not statistically significant within WHR categories. BMI was also not associated with CRC risk in women and with rectal cancer after mutual adjustment. Conversely, WHR was strongly associated with CRC risk in both sexes and with both colon and rectal cancer risk before and after adjustment for BMI. BMI and WC could not be mutually adjusted for due to their high correlation.

Central obesity is a much stronger predictor of CRC and may account for most of the CRC risk linked to obesity. Our findings also emphasize the need for incorporating measures such as WHR alongside BMI in clinical practice to improve obesity prevention and management.

Although the association between excess weight and cancer risk is well established, it is not known how this association evolves across the lifespan. We aimed to investigate the strength of the association of excess weight at different ages in adulthood and adult weight gain with cancer risk.

We used data from a German population-based cohort study of 9,218 participants aged 50-75 (mean 62) years recruited between 2000 and 2002. Participants provided socio-demographic, medical, and lifestyle data, including self-reported current height and weight (at ages 20, 30, 40, 50 and baseline). Main exposures were body mass index (BMI, kg/m2) at different ages and weight change (kg) since age 20. The outcome was obesity-related cancer (13 types). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox models.

During a median follow-up of 17.1 years, 852 diagnoses of obesity-related cancers were recorded. Overweight and obesity in early and middle adulthood showed no significant associations with obesity-related cancer risk, whereas significant positive associations were observed for overweight and obesity at age 50 years and older. For weight change since age 20, strong associations were found, with HRs (95% CI) of 1.42 (1.11-1.81), 1.57 (1.24-1.99) and 1.96 (1.56-2.47) for the 2nd, 3rd, and 4th quartile compared to the lowest quartile, respectively. After mutual adjustment for adult weight gain and BMI at baseline, the estimates for weight gain persisted, while those for BMI at baseline disappeared. The main limitation of the study is that the weights were self-reported.

Our findings suggest that excess weight may have a varying effect on cancer risk through life with its impact potentially being more pronounced in later adulthood, and that adulthood weight gain might be a better indicator of obesity-related cancer risk than BMI measured at a single point in time.

The response rate of immune checkpoint blockade (ICB) therapy for non-small-cell lung cancer (NSCLC) remains limited. Recent evidence suggests that obese cancer patients are more likely to benefit from ICB therapy, however, the specific mechanism needs further research. In this study, we found that anti-PD-1 therapy was more effective in obese NSCLC patients compared to normal weight patients and this was verified in mouse NSCLC model. Further bioinformatics analysis indicated that the glycolytic metabolism was markedly elevated in obese NSCLC patients. In vitro co-culture experiment showed that both increased glycolysis of tumor cells and external addition of lactate promoted T cell PD-1 expression. And, PD-1 upregulation was related to monocarboxylate transporter 1 (MCT1)-mediated lactate transport and subsequent lysine lactylation of histones in T cells. Based on the aforementioned data, our study contributes to better application of anti-PD-1 therapy in NSCLC.

Individual traits and habits have shown to be associated with health and health behaviour. One such habit is how individuals use music. This study aimed to examine if using music as a mood regulator is related to risk factors of lifestyle diseases. Participants who joined the present Motivation Makes the Move! lifestyle intervention were overweight and sedentary adults (n = 76, ages 19-40). They answered questionnaires about physical activity and use of music. They also underwent a cardiopulmonary exercise test and their body composition was assessed. Additionally, the analyses' robustness was tested through controlling for physical, sociodemographic and psychological health related factors. We observed that despite the participants' self-reported commitment to regular physical activity, their fitness level was poor. Using music as a mood regulator was associated with lower cardiorespiratory fitness. Use of music was also positively linked to body fat percentage, although this finding did not remain significant after adjusting for age, educational level and experienced health. We urge future research to address the relationship between music use and risk factors of lifestyle diseases in a population sample.

The objective of this study was to estimate cancer burden attributable to excess body weight (EBW) and identify its main source.

We obtained relative risks from meta-analyses, cancer and population data from the Global Burden of Disease Study (GBD) 2021, and BMI prevalence data from the NCD Risk Factor Collaboration (NCD-RisC). We calculated the incidence of 11 cancers attributable to high BMI from 1990 to 2021, analyzed trends using joinpoint regression, and assessed cohort effects with the age-period-cohort model. Decomposition analysis was conducted by cancer-specific risk factors and by population size, aging, and epidemiological changes.

The incidence of 11 EBW-related cancers has increased from 1990 to 2021. Later-born cohorts and older age groups had higher cancer incidence rates. High BMI was the top contributor to changes in cancer burden (15.96% of all disability-adjusted life years [DALYs]), particularly in high Sociodemographic Index (SDI) regions. Colorectal, esophageal, and liver cancer had the highest burden due to high BMI (1,349,622; 1,284,385; and 944,616 DALYs, respectively). Epidemiological changes in BMI contributed to the rising DALY burden, ranging from 7.88% for postmenopausal breast cancer to 49.20% for liver cancer.

The rising prevalence of EBW contributed to the global cancer burden, showing a significant birth cohort effect. High BMI was the top contributing factor to obesity-related cancers, surpassing other epidemiological risk factors.

Tumors exhibit an increased ability to obtain and metabolize nutrients. Here, we implant engineered adipocytes that outcompete tumors for nutrients and show that they can substantially reduce cancer progression, a technology termed adipose manipulation transplantation (AMT). Adipocytes engineered to use increased amounts of glucose and fatty acids by upregulating UCP1 were placed alongside cancer cells or xenografts, leading to significant cancer suppression. Transplanting modulated adipose organoids in pancreatic or breast cancer genetic mouse models suppressed their growth and decreased angiogenesis and hypoxia. Co-culturing patient-derived engineered adipocytes with tumor organoids from dissected human breast cancers significantly suppressed cancer progression and proliferation. In addition, cancer growth was impaired by inducing engineered adipose organoids to outcompete tumors using tetracycline or placing them in an integrated cell-scaffold delivery platform and implanting them next to the tumor. Finally, we show that upregulating UPP1 in adipose organoids can outcompete a uridine-dependent pancreatic ductal adenocarcinoma for uridine and suppress its growth, demonstrating the potential customization of AMT.

Periprostatic adipose tissue (PPAT) contributes to the pathogenesis of prostate cancer. The purpose of this study was to review and summarize the literature on the role of PPAT in prostate cancer pathogenesis. Moreover, we evaluated the clinical implication of PPAT in patients with prostate cancer. We performed a scoping literature review of PubMed from January 2002 to November 2024. Search terms included "periprostatic adipose tissue", "adipokines", and "prostate cancer". Secondary search involved reference lists of eligible articles. The key criterion was to identify studies that included PPAT, adipokines, and their role in prostate cancer biology and clinical features. In total 225 publications were selected for inclusion in this review. The studies contained in publications allowed us to summarize the data on the pathogenesis of PPAT as a contributor to prostate cancer biology and its aggressiveness. The review also presents new research directions for PPAT as a new target for the treatment of prostate cancer. Based on the current review, it can be stated that PPAT plays an important role in prostate cancer pathogenesis. Moreover, PPAT seems to be a promising target point when it comes to finding new therapies in patients with more aggressive and/or advanced stages of prostate cancer.

Obesity, classified by body mass index (BMI), is associated with higher postmenopausal breast cancer (BCa) risk. Yet, the associations between abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) with BCa are unclear.

We assessed BCa associations with abdominal VAT and SAT in a prospective cohort of postmenopausal women without a history of cancer and with 27 years follow-up (N = 9950), during which all new cancers were adjudicated. Dual-energy x-ray absorptiometry scans assessed adiposity at baseline, year 3, and year 6. Competing-risks multivariable sub-hazard ratios (SHR), with adjustments for sociodemographic, behavioral, reproductive, and anthropometric characteristics, were estimated for baseline and time-dependent associations between VAT, SAT, and incident BCa.

Participants averaged 63.3 ± 7.4 years of age and a BMI of 28.20 ± 5.72 kg/m2 at baseline. The models included 738 incident BCa case patients (N = 593 invasive; N = 145 in situ). Baseline VAT and SAT area were associated with statistically significantly increased BCa risk, by 36% and 19%, respectively. Increasing VAT/SAT ratio was associated with an 8% increase in incident BCa. Time-dependent models produced similar results. VAT and VAT/SAT associated BCa risk was highest for African American/Black women, although not statistically significantly different from other groups. Quartiles (Q) of VAT/SAT were also explored; the SHR for Q4 compared with Q1 was 1.49 (95% CI = 1.18 to 1.87).

Higher abdominal VAT and SAT are associated with an increased risk of postmenopausal BCa, and VAT/SAT may provide a distinctive risk estimate. Potential racial and ethnic differences require replication in a larger sample (Women's Health Initiative; NCT00000611; https://clinicaltrials.gov/study/NCT00000611).

The proportion of colorectal cancer (CRC) cases attributable to excess weight, known as population attributable fraction (PAF), has been commonly based on measures of body mass index (BMI). Central obesity metrics, such as waist circumference (WC) and waist to hip ratio (WHR), are potentially better indicators of adiposity and have demonstrated stronger associations with CRC incidence.

To examine PAFs of CRC cases that are attributable to high WC and WHR and compare them to those attributable to high BMI.

This population-based UK Biobank cohort study included 458 543 individuals aged 40 to 69 years at recruitment (March 2006 to July 2010) living within a reasonable distance of the 22 assessment centers across the UK. The analyses were conducted between May and July 2024.

Exposures were BMI, as a measure of general obesity, and WC and WHR, as indicators of central obesity.

Hazard ratios (HRs) and corresponding 95% CIs were calculated for the associations of BMI, WC, and WHR with CRC incidence. The PAFs and 95% CIs of CRC cases attributable to high BMI, WC, and WHR were also calculated.

A total of 458 543 participants (median [IQR] age, 57 [50-63] years; 244 351 [53.3%] female) were included in the study. During a median follow-up of 11.8 (IQR, 10.9-12.5) years, 5944 participants were diagnosed with CRC. The HRs for the association with CRC incidence were notably smaller for BMI (HR for the highest vs lowest BMI quartile, 1.23; 95% CI, 1.14-1.33) than for WC (HR for the highest vs lowest WC quartile, 1.37; 95% CI, 1.27-1.49) and WHR (HR for the highest vs lowest WHR quartile, 1.40; 95% CI, 1.29-1.51); these associations became comparable only after accounting for possible reverse causality by excluding the initial years of follow-up. Similarly, the PAF of CRC for high BMI was 9.9% (95% CI, 5.5%-14.4%), substantially lower than the PAFs for high WC and WHR, which were 17.3% (95% CI, 12.3%-22.1%) and 17.6% (95% CI, 12.9%-22.2%), respectively. After excluding the initial 7 years of follow-up, PAF estimates became analogous across all measures of obesity and were 15.7% (95% CI, 8.9%-22.4%) for BMI, 16.9% (95% CI, 9.8%-23.8%) for WC, and 18.0% (95% CI, 11.5%-24.6%) for WHR.

In this cohort study of approximately half a million participants, the PAF of CRC attributable to excess weight, defined as high BMI, was considerably underestimated. The PAFs attributable to WC and WHR were consistent and much higher, underlining the importance of efforts to limit and overcome the obesity epidemic in CRC prevention.

Understanding how obesity impacts human mammary adipose tissue (MAT) biology is crucial for deciphering its role in mammary epithelium during both physiological and pathophysiological processes, including breast cancer. Hypertrophic mammary adipocytes and Crown-Like Structures are present in MAT of patients with obesity but whether these changes initiate a fibro-inflammatory response at the tissue level remains insufficiently explored.

We investigated the markers of adipose tissue dysfunction (immune cell infiltration, secretion pattern and fibrosis) in tumor-free MAT of patients with obesity versus patients who are lean.

Tumor-free MAT were obtained from 96 women with (n = 43) or without (n = 53) obesity who underwent mastectomy for breast cancer risk reduction or treatment. Immune and non-immune cell infiltration were determined using flow cytometry. Bulk transcriptomic was used to characterize the phenotype of CD206+ macrophages whose infiltration is increased in patients with obesity. Conditioned-medium were prepared from MAT to characterize their secretome and dose adipokines and cytokines by ELISA assay. The extra-cellular matrix (ECM) deposition was evaluated by Masson trichrome staining on cross-stained sections, 3D imaging of red picrosirius-stained tissues and measure of hydroxyproline content.

We observed an increase of CD206+/HLA-DR+ macrophages in the stromal vascular fraction of MAT from patients with obesity compared to patients who are lean. Other immune cell infiltration and endothelial or adipose progenitor cell numbers were similar between groups. Bulk transcriptomics on CD206+ macrophages revealed a significant decrease in ECM component expression and processing in obesity. In addition, no heightened secretion of pro-inflammatory cytokines, TGF-β1 or MCP-1 was observed in the samples from patients with obesity. ECM characterization revealed an absence of fibrosis, with MAT of patients with obesity showing even a slightly reduced collagen secretion and deposition compared with their lean counterparts.

Obesity is not associated with inflammation nor fibrosis in MAT, highlighting its unique behavior.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by defective lipid metabolism, which causes disease progression. MASH is also linked to various cardiometabolic risk factors, including obesity and type 2 diabetes. The contribution of defective lipid metabolism in MASH to cardiometabolic comorbidities is incompletely understood. Using hepatic lipidome profiling in eight mouse strains that differ in MASH susceptibility and patients with MASH, we show that phosphatidylserine (PS) accumulation and preservation of PS synthase 1 (PSS1) expression is associated with resistance to MASH and hypertriglyceridemia. Mechanistically, hepatocyte-specific PSS1 overexpression remodels the hepatic and very-low-density lipoprotein (VLDL) lipidome in mice with MASH. Specifically, we show an increase in VLDL ceramide that suppresses the expression and activity of lipoprotein lipase in skeletal muscle, thereby reducing VLDL-triglyceride clearance, fatty acid uptake, and lipid accumulation in muscle, overall exacerbating hypertriglyceridemia. Together, the results of this study identify hepatic PSS1 as a regulator of systemic lipoprotein metabolism.

Obesity is recognized as a significant risk factor for various types of cancer. Although the incidence of some types of cancer across various primary sites is decreasing due to specific prevention measures (screening programs, smoking cessation), the incidence of neoplasms in the young population shows a significant increase associated with obesity. There is sufficient evidence to say that bariatric surgery has been shown to significantly lower the risk of developing obesity-associated cancers, which are linked to metabolic dysregulation, chronic low-grade systemic inflammation, and hormonal alterations such as elevated levels of insulin and sex hormones.

Adiposity is positively associated with risk of some cancer sites and other health conditions in men; however, it is unclear if endogenous hormones play a role in these associations. We examined how body composition, measured from magnetic resonance imaging (MRI) and common measures of adiposity (e.g., body mass index (BMI)), are related to hormone concentrations in men from the UK Biobank study.

Up to 16,237 men with available body composition data (including visceral, subcutaneous, and liver fat, muscle fat infiltration (MFI), lean tissue, and common adiposity measures) and serum hormone measurements (insulin-like growth factor-I (IGF-I), total testosterone, sex hormone-binding globulin (SHBG), and calculated free testosterone) were included. Multivariable-adjusted linear regression models were used to determine the geometric mean hormone and SHBG concentrations across categories of each exposure.

Common measurements of adiposity were highly correlated with MRI measures of central and total adiposity (r = 0.76-0.91), although correlations with ectopic fat (liver fat and MFI) were lower (r = 0.43-0.54). Most adiposity measurements showed an inverse U- or J-shaped association with circulating IGF-I and free testosterone; however, MFI was linearly inversely associated, and lean tissue volume was positively associated with both IGF-I and free testosterone concentrations. All body composition measures were inversely associated with total testosterone and SHBG concentrations (relative geometric mean difference between Q5 vs. Q1: 20-30%).

Our results show that common adiposity and most MRI measures of adiposity relate similarly to serum hormone concentrations; however, associations with ectopic fat (particularly MFI) and lean tissue were different.

Endometrial and Ovarian cancers are two highly prevalent and fatal reproductive diseases with poor prognoses among women. Elevated estrogen levels in Ovarian Cancer (OC) stimulate the endometrium, causing Endometrial Cancer (EC). Although numerous studies have reported the crucial genes and pathways in this cancer, the pathogenesis of this disease remains unclear. In this study, used bioinformatics tools to analyse GSE63678, GSE115810, GSE36389, GSE26712, GSE36668, GSE27651, GSE6008, GSE69429, GSE69428, GSE18521, GSE185209, GSE54388 gene expression microarray datasets for both the cancers. We analyzed the differential gene expression, functional association, and structural studies. The analysis identified crucial differentially expressed genes (DEGs) in both cancers associated with DNA damage, DNA integrity, and cell-cycle checkpoint signaling pathways. CLDN7, UBE2I, WT1, JAM2, FOXL2, F11R, JAM3, ZFPM2, MEF2C, and PIAS1 are the top 10 hub genes commonly identified in both cancer types. Only CLDN7 and F11R are upregulated, whereas the remaining hub genes are downregulated in both cancers, suggesting a common framework for contributing to tumorigenesis. Molecular docking and dynamics were performed on the UBE2I protein with Irinotecan Hydrochloride, which could serve as the new approach for treating and managing both cancers. The study reveals the common molecular pathways, pointing out the role of cell cycle and DNA damage and integrity checkpoint signaling in the pathogenesis of both cancer types. This study explored the UBE2I gene as a potential biomarker in OC and EC. Further, this study concludes that the irinotecan hydrochloride drug has higher therapeutic effects on UBE2I protein through docking and dynamics studies.

The adipose tissue is a complex organ that can play endocrine, metabolic, and immune regulatory roles in cancer. In particular, adipocytes provide metabolic substrates for cancer cell proliferation and produce signaling molecules that can stimulate cell adhesion, migration, invasion, angiogenesis, and inflammation. Cancer cells, in turn, can reprogram adipocytes towards a more inflammatory state, resulting in a vicious cycle that fuels tumor growth and evolution. These mechanisms are enhanced in obesity, which is associated with the risk of developing certain tumors. Diet, an exogenous source of lipids with pro- or anti-inflammatory functions, has also been connected to cancer risk. This review analyzes how adipocytes and lipids are involved in tumor development and progression, focusing on the relationship between obesity and cancer. In addition, we discuss how diets with varying lipid intakes can affect the disease outcomes. Finally, we introduce novel metabolism-targeted treatments and adipocyte-based therapies in oncology.

Elevated body mass index (BMI) ≥25 kg/m2 is a major preventable cause of cancer. A single BMI measure does not capture the degree and duration of exposure to excess BMI. We investigate associations between adulthood overweight-years, incorporating exposure time to BMI ≥25 kg/m2, and cancer incidence, and compare this with single BMI.

In this cohort study and individual participant data meta-analysis, we obtained data from the ABACus 2 Consortium, consisting of four US cohorts: Atherosclerosis Risk in Communities (ARIC) study (1987-2015), Women's Health Initiative (WHI; 1991 to 2005 [main study], to 2010 [Extension 1], and to 2020 [Extension 2]), Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial (1993-2009), NIH-AARP Diet and Health Study (1996-2011), and one European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC; participants enrolled in 1990 and administrative censoring was centre-specific). Participants with at least 3 BMI measurements and complete cancer follow-up data were included. We calculated overweight-years: degree of overweight (BMI ≥25 kg/m2) multiplied by the duration of overweight (years). Using random effects two-stage individual participant data meta-analyses, associations between cancer and overweight-years, single BMI, cumulative overweight degree and duration, measured at the same time and captured over a median of 41 years in men and 39 years in women, were evaluated with Cox proportional hazards models. Models were age-adjusted or multivariable (MV) adjusted for baseline age, ethnicity, alcohol, smoking and hormone replacement therapy (HRT). Harrell's C-statistic of metrics were compared. This study is registered at PROSPERO, CRD42021238270.

720,210 participants, including 312,132 men and 408,078 women, were followed up for cancer incidence over a median 9.85 years (interquartile range (IQR) 8.03, 11.67) in men and 10.80 years (IQR 6.05, 15.55) in women. 12,959 men (4.15%) and 36,509 women (8.95%) were diagnosed with obesity-related cancer. Hazard ratios for obesity-related cancers in men, per 1 standard deviation (SD) overweight-years were 1.15 (95% CI: 1.14, 1.16, I2: 0) age-adjusted and 1.15 (95% CI: 1.13, 1.17, I2: 0%) MV-adjusted and per 1SD increment in single BMI were 1.17 (95% CI: 1.16, 1.18, I2: 0) age-adjusted and 1.16 (95% CI: 1.15, 1.18, I2: 0%) MV-adjusted. The HR for overweight-years in women per 1 SD increment was 1.08 (95% CI: 1.04, 1.13, I2: 82%) age-adjusted and 1.08 (95% CI: 1.04, 1.13, I2: 83%) MV-adjusted and per 1SD increment in single BMI was 1.10 (95% CI: 1.07, 1.14, I2: 72%) age-adjusted and 1.11 (95% CI: 1.07, 1.15, I2: 79%) MV-adjusted. C-statistics for overweight-years and single BMI for obesity-related cancers were 0.612 (95% CI: 0.578, 0.646) and 0.611 (95% CI: 0.578, 0.644) respectively for men and 0.566 (95% CI: 0.534, 0.598) and 0.573 (95% CI: 0.546, 0.600) for women.

Adulthood degree and duration of excess BMI were associated with cancer risk. Both factors should be considered in cancer prevention strategies and policies. This study only focused on adulthood exposure to excess BMI, so the minimal differences in the predictive performance between adiposity metrics may be due to underestimation of cumulative excess BMI exposure.

Cancer Research UK, the Manchester NIHR Biomedical Research Centre, the National Cancer Institute, the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, U.S. Department of Health and Human Services, the Intramural Research Program of the National Cancer Institute, the International Agency for Research on Cancer, Imperial College London, European Commission (DG-SANCO), the Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, the Hellenic Health Foundation, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Health Research Fund, Instituto de Salud Carlos III, regional Spanish governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, the Catalan Institute of Oncology, Swedish Cancer Society, Swedish Scientific Council, and Region Skåne and Region Västerbotten, and the Medical Research Council.

Endometrial cancer (EC) is the most common gynecological malignancy, with rising incidence and mortality rates. Key risk factors, including obesity, prolonged estrogen exposure, and metabolic disorders, underscore the urgent need for non-invasive, early diagnostic tools. This review focuses on the role of DNA methylation as a potential biomarker for early EC detection. Aberrant DNA methylation in the promoter regions of tumor suppressor genes can lead to gene silencing and cancer progression. We examine recent studies utilizing minimally invasive samples, such as urine, cervicovaginal, and cervical scrapes, to detect early-stage EC through DNA methylation patterns. Markers such as RASSF1A, HIST1H4F, GHSR, SST, and ZIC1 have demonstrated high diagnostic accuracy, with AUC values up to 0.95, effectively distinguishing EC from non-cancerous conditions. This review highlights the potential of DNA methylation-based testing as a non-invasive alternative to traditional diagnostic methods, offering earlier detection, better risk stratification, and more personalized treatment plans. These innovations hold the promise of transforming clinical practice by enabling more timely and effective management of endometrial cancer.

Insulin resistance is associated with increased levels of IGF-1. IGF-1 has been shown to increase the risk of laryngeal squamous cell carcinoma. The Triglyceride-glucose index (TyG index) is a marker of insulin resistance. Our study aimed to investigate the relationship between the TyG index and laryngeal squamous cell carcinoma.

Retrospective cohort study.

Two tertiary care academic hospitals.

The study included 53 patients with laryngeal squamous cell carcinoma (Group 1) and 48 healthy volunteers (Group 2). Laryngeal cancer patients were divided into two groups according to their stage. Stages I and II were named Group 1A, and Stages III and IV were called Group 1B. The TyG index was calculated as ln [fasting Triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. The effect of the TyG index on laryngeal cancer was investigated on the parameters of sex, age, body mass index, and stage of the disease.

There were no significant differences in age, sex, and BMI between the groups. The TyG index of group 1 (4.75 ± 0.33) was significantly higher than that of group 2 (4.59 ± 0.15). The TyG index value of group 1B (4.84 ± 0.31) was significantly higher than both group 1A (4.61 ± 0.32) and group 2 (4.59 ± 0.15). There was no significant difference between the TyG index values of group 1A (4.61 ± 0.32) and group 2 (4.59 ± 0.15).

The TyG index may be a promising laryngeal squamous cell carcinoma biomarker. People with a higher TyG index may have a higher incidence of laryngeal squamous cell carcinoma and a higher risk of progression.

Numerous recent studies have explored the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of various extrahepatic cancers. However, the conclusions were inconclusive. The aim of this study was to clarify this relationship by conducting a robust meta-analysis.

Systematic searches were conducted on PubMed, Embase and Web of Science databases to identify relevant cohort studies published prior to February 2024. Hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were combined using a random-effects model in this meta-analysis.

Eighteen cohort studies (approximately 16.7 million participants) were finally included in this meta-analysis. MASLD was linked to a higher risk of extrahepatic cancers, such as gastric (n = 10, HR = 1.47, 95% CI: 1.07-2.01), colorectal (n = 13, HR = 1.33, 95% CI: 1.16-1.53), pancreatic (n = 8, HR = 1.41, 95% CI: 1.11-1.79), biliary tract (n = 5, HR = 1.27, 95% CI: 1.18-1.37), thyroid (n = 6, HR = 1.46, 95% CI: 1.02-2.09), urinary system (n = 10, HR = 1.45, 95% CI: 1.25-1.69), breast (n = 11, HR = 1.17, 95% CI: 1.08-1.26) and female genital organ cancers (n = 10, HR = 1.36, 95% CI: 1.11-1.66). However, there was no statistically significant association between MASLD and the risk of head and neck (n = 6, HR = 1.03, 95% CI: 99-1.07), oesophageal (n = 9, HR = 1.26, 95% CI: 0.86-1.86), lung (n = 9, HR = 1.01, 95% CI: 0.92-1.10), prostate (n = 9, HR = 1.06, 95% CI: 0.94-1.19) or small intestine cancer (n = 2, HR = 1.75, 95% CI: 1.00-3.06).

This latest large-scale meta-analysis indicated that MASLD was associated with an increased risk of various extrahepatic cancers, such as gastric, colorectal, pancreatic, biliary duct, thyroid, urinary system, breast, skin and female genital cancers. Further research is needed to investigate the mechanisms underlying these associations.

The effects of physical activity on the development of different types of cancers have not been comprehensively studied. This nationwide, population-based cohort study investigated the effects of leisure-time physical activity (LTPA) on the development of different types of cancer in Taiwanese adults. A total of 67,890 adult participants (≥ 18 y old) from five rounds (2001, 2005, 2009, 2013, and 2017) of the Taiwan National Health Interview Survey were included. LTPA was measured as the metabolic equivalent of task (MET) expenditure per week and was classified as inactive (< 1 MET-h), low (1-7.49 MET-h), or high (≥ 7.5 MET-h). The LTPA and other covariates were collected through in-person interviews at baseline. New-onset cancer was ascertained from histopathological reports. The Fine-Gray sub-distribution method, with death as a competing risk, was used to determine the impact of LTPA on incident cancer risk.

During the 844,337 person-years of follow-up, 4,435 individuals developed cancer. Compared to inactive adults, individuals engaging in high levels of LTPA (≥ 7.5 MET-h/week) were significantly associated with a reduced risk of developing cancer (adjusted hazard ratio [aHR] = 0.93; 95% confidence interval [CI] = 0.87-0.99). However, those with low levels of LTPA (1-7.49 MET-h/week) did not exhibit a significant association with a reduced risk of developing cancer (aHR = 1.00; 95% CI = 0.92-1.10). When considering specific types of cancers, participants with high levels of LTPA (≥ 7.5 MET-h/week) had a significantly lower risk of developing bladder cancer (aHR = 0.68; 95% CI = 0.47-0.99), cervical cancer (aHR = 0.48; 95% CI = 0.24-0.95), and thyroid cancer (aHR = 0.64; 95% CI = 0.44-0.93).

Our findings suggest that high LTPA (≥ 7.5 MET-h/week) is significantly associated with a low risk of incident bladder, cervical, and thyroid cancers.

Obesity is a disease with deleterious effects on the female reproductive tract, including the endometrium.

We sought to understand the effects of excess adipose on the benign endometrium.

A physiologic in vitro coculture system was developed, consisting of multicellular human endometrial organoids, adipose spheroids, and menstrual cycle hormones. Native human endometrial tissue samples from women with and without obesity were also analyzed. Benign endometrial tissues from premenopausal women ages 33 to 53 undergoing hysterectomy were obtained following written consent at Northwestern University Prentice Women's Hospital, Chicago, Illinois. Gene expression, protein expression, chromatin binding, and expression of DNA damage and oxidative damage markers were measured.

Under high adiposity conditions, endometrial organoids downregulated endometrial secretory phase genes, suggestive of an altered progesterone response. Progesterone specifically upregulated the metallothionein (MT) gene family in the epithelial cells of endometrial organoids, while high adiposity significantly downregulated the MT genes. Silencing MT genes in endometrial epithelial cells resulted in increased DNA damage, illustrating the protective role of MTs. Native endometrium from women with obesity displayed increased MT expression and oxidative damage in the stroma and not in the epithelium, indicating the cell-specific impact of obesity on MT genes.

Taken together, the in vitro and in vivo systems used here revealed that high adiposity or obesity can alter MT expression by decreasing progesterone response in the epithelial cells and increasing oxidative stress in the stroma.

Cholelithiasis is the most well-recognized risk factor for gallbladder cancer (GBC), the predominant biliary-tract malignancy; however, credibility on other modifiable exposures remains uncertain. We performed a field-wide systematic review and meta-analysis on environmental factors associated with GBC.

We systematically searched Medline/PubMed and Embase up to May 8, 2023, to identify randomized and nonrandomized studies examining environmental factors for GBC. We conducted random-effects meta-analyses focusing on longitudinal studies. Evidence from case-control studies was considered complementary. Evidence credibility was graded by prespecified criteria including the random-effects estimate, 95% confidence interval (CI), P value, statistical heterogeneity, small-study effects, and robustness to unmeasured confounding.

We identified 215 eligible primary studies and performed 350 meta-analyses across 7 domains: lifestyle, reproductive, metabolic, dietary, infections, interventions, and contaminants and occupational exposures. Based on longitudinal evidence, body mass index (relative risk [RR] per 5-unit increase, 1.27; 95% CI, 1.21‒1.33), hip circumference (RR per 5-cm increase, 1.16; 95% CI, 1.11‒1.22), infection of bile ducts (RR, 31.7; 95% CI, 24.8-40.6), high parity (RR, 1.48; 95% CI, 1.30‒1.68), obesity (RR, 1.70; 95% CI, 1.44‒2.01), overweight (RR, 1.28; 95% CI, 1.14‒1.43), waist circumference (RR per 5-cm increase, 1.14; 95% CI, 1.10‒1.18), and waist-to-height ratio (RR per 0.1 increase, 1.49; 95% CI, 1.36‒1.64) were robustly associated with increased GBC risk, whereas high education (RR, 0.63; 95% CI, 0.49‒0.82) was associated with reduced risk (moderate-to-high credibility). Another 39 significant associations showed lower credibility, including different exposure scenarios of tobacco smoking, alcohol consumption, and insufficient physical activity.

This study offers a detailed appraisal and mapping of the evidence on modifiable factors for GBC. Further high-quality prospective studies are essential to validate emerging associations and inform preventive strategies in high-incidence areas. (Systematic review registration: CRD42023434673.).

Type 2 diabetes mellitus (T2DM) and cancer share common risk factors including obesity, inflammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate the PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and anti-apoptosis. The inhibition of the PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy; however, drug resistance poses a major problem in clinical settings resulting in limited efficacy of agents; thus, combination treatments with therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.

(1) Background: Young-onset colorectal adenomas (YOAs) are precursors to early-onset colorectal cancer, a growing concern among individuals under 50 years old. This study investigated the association between surrogate markers of insulin resistance (IR) and YOAs occurrence. (2) Methods: A retrospective cross-sectional analysis was conducted on 4467 individuals aged 20 to 49 years who underwent their first screening colonoscopy at Dong-A University Hospital from 2018 to 2022. IR was assessed using the triglyceride-glucose (TyG) index, triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C), and metabolic score for insulin resistance (METS-IR). (3) Results: Individuals with YOAs exhibited significantly higher median TyG index (8.51 ± 0.71 vs. 8.32 ± 0.61, p < 0.001), TG/HDL-C ratio (2.78 ± 3.05 vs. 2.12 ± 1.85, p < 0.001), and METS-IR (35.72 ± 8.37 vs. 33.44 ± 9.11, p < 0.001) values than controls. The adjusted odds ratios for YOAs were 1.064 (95% CI: 1.22-2.23, p = 0.021) for the TyG index, 1.067 (95% CI: 1.031-1.105, p < 0.001) for the TG/HDL-C ratio, and 1.011 (95% CI: 1.002-1.021, p = 0.023) for METS-IR values, indicating a strong association between higher IR marker values and the presence of YOAs. (4) Conclusions: Elevated IR marker values are strongly associated with the occurrence of YOAs in individuals under 50 years old.

Sex disparity between metabolic-obesity (defined by body mass index, BMI) phenotypes and obesity-related cancer (ORC) remains unknown. Considering BMI reflecting overall obesity but not fat distribution, we aimed to systematically assess the association of our newly proposed metabolic-anthropometric phenotypes with risk of overall and site-specific ORC by sex.

A total of 141,579 men (mean age: 56.37 years, mean follow-up time: 12.04 years) and 131,047 women (mean age: 56.22 years, mean follow up time: 11.82 years) from the UK Biobank was included, and designated as metabolic-anthropometric phenotypes based on metabolic status (metabolically healthy/unhealthy), BMI (non-obesity/obesity) and body shape (pear/slim/apple/wide). The sex-specific association of different phenotypes with overall and site-specific ORC was assessed by hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression models.

We found metabolically unhealthy and/or obesity phenotypes conveyed a higher risk in men than in women for overall ORC and colorectal cancer compared with metabolically healthy non-obesity phenotype (Pinteraction < 0.05). Of note, metabolically healthy obesity phenotype contributed to increased risks of most ORC in men (HRs: 1.58 ~ 2.91), but only correlated with higher risks of endometrial (HR = 1.89, 95% CI: 1.54-2.32) and postmenopausal breast cancers (HR = 1.17, 95% CI: 1.05-1.31) in women. Similarly, even under metabolically healthy, men carrying apple and wide shapes phenotypes (metabolically healthy apple/wide and metabolically healthy non-obesity apple/wide) suffered an increased risk of ORC (mainly colorectal, liver, gastric cardia, and renal cancers, HRs: 1.20 ~ 3.81) in comparison with pear shape or non-obesity pear shape.

There was a significant sex disparity between metabolic-anthropometric phenotypes and ORC risk. We advised future ORC prevention and control worth taking body shape and sex disparity into account.

The present study aimed to assess the risk of postmenopausal breast cancer in women based on a combination of body mass index (BMI) and high-sensitivity C-reactive protein (hs-CRP) levels. A total of 20,400 participants were investigated as part of the 'Kailuan Study' clinical trial. Participants were classified into four groups based on BMI (BMI ≥24 or <24 kg/m2) and hs-CRP level (hs-CRP ≥3 or <3 mg/l). Cox proportional hazards models were used to evaluate the association between the combination of BMI and hs-CRP and the risk of postmenopausal breast cancer. A total of 19,540 participants met the inclusion criteria. The median follow-up time was 14.97 years, with a cumulative follow-up period of 283,599.43 person-years. Among the participants, 269 individuals were diagnosed with postmenopausal breast cancer. Individuals with a high BMI (BMI ≥24 kg/m2) and a high hs-CRP level (hs-CRP ≥3 mg/) had a greater risk of postmenopausal breast cancer compared with individuals with a low BMI (BMI <24 kg/m2) and a low hs-CRP level (<3 mg/l) (hazard ratio, 1.75; 95% confidence interval, 1.25-2.47). The sensitivity analysis showed findings consistent with the primary results. In conclusion, the combination of high BMI and high hs-CRP level is associated with an increased risk of postmenopausal breast cancer. The present study is part of the Kailuan Study. Trial registration number: ChiCTRTNCR11001489 (Chinese Clinical Trial Registry, https://www.chictr.org.cn/showproj.html?proj=8050). Date of registration: 19/07/2015.

Excess body weight may modulate the progression of various cancer types. The prognostic relevance of body mass index (BMI) has not been fully examined in patients with biliary tract cancer.

Using a single-institutional cohort of 360 patients receiving gemcitabine-based chemotherapy for advanced biliary tract cancer, we examined the association of BMI with overall survival (OS). Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for OS according to BMI. The findings were validated using a Japanese nationwide inpatient database including 8324 patients treated at 201 hospitals.

In the clinical cohort, BMI was not associated with OS (Ptrend = 0.34). Compared to patients with BMI = 18.5-24.9 kg/m2, patients with BMI < 18.5 kg/m2 and ≥ 25.0 kg/m2 had adjusted HRs for OS of 1.06 (95% CI, 0.78-1.45) and 1.01 (95% CI, 0.74-1.39), respectively. There was no evidence on a non-linear relationship between BMI and OS (Pnonlinearity = 0.63). In the nationwide cohort, the null findings were validated (Ptrend = 0.18) with adjusted HRs of 1.07 (95% CI, 0.98-1.18) for BMI < 18.5 kg/m2 and 1.05 (95% CI, 0.96-1.14) for BMI ≥ 25.0 kg/m2 (vs. BMI = 18.5-24.9 kg/m2). In the clinical cohort, BMI was not associated with progression-free survival (Ptrend = 0.81).

BMI was not associated with survival outcomes of patients with advanced biliary tract cancer. Further research is warranted incorporating more detailed body composition metrics to explore the prognostic role of adiposity in biliary tract cancer.

1,25(OH)2D3 is a fat-soluble vitamin, involved in regulating Ca2+ homeostasis in the body. Its storage in adipose tissue depends on the fat content of the body. Obesity is the result of abnormal lipid deposition due to the prolonged positive energy balance and increases the risk of several cancer types. Furthermore, it has been associated with vitamin D deficiency and defined as a low 25(OH)2D3 blood level. In addition, 1,25(OH)2D3 plays vital roles in Ca2+-Pi and glucose metabolism in the adipocytes of obese individuals and regulates the expressions of adipogenesis-associated genes in mature adipocytes.

The present contribution focused on the VDR mediated mechanisms interconnecting the obese condition and cancer proliferation due to 1,25(OH)2D3-deficiency in humans. This contribution also summarizes the identification and development of molecular targets for VDR-targeted drug discovery.

Several studies have revealed that cancer development in a background of 1,25(OH)2D3 deficient obesity involves the VDR gene. Moreover, 1,25(OH)2D3 is also known to influence several cellular processes, including differentiation, proliferation, and adhesion. The multifaceted physiology of obesity has improved our understanding of the cancer therapeutic targets. However, currently available anti-cancer drugs are notorious for their side effects, which have raised safety issues. Thus, there is interest in developing 1,25(OH)2D3-based therapies without any side effects.

SARIFA was very recently introduced as a histomorphological biomarker with strong prognostic power for colorectal, gastric, prostate, and pancreatic cancer. It is characterized by the direct contact between tumor cells and adipocytes due to a lack of stromal reaction. This can be easily evaluated on routinely available H&E-slides with high interobserver agreement. SARIFA also reflects a specific tumor biology driven by metabolic reprogramming. Tumor cells in SARIFA-positive tumors benefit from direct interaction with adipocytes as an external source of lipids. Numerous studies have shown that lipid metabolism is crucial in carcinogenesis and cancer progression. We found that the interaction between tumor cells and adipocytes was not triggered by obesity, as previously assumed. Instead, we believe that this is due to an immunological mechanism. Knowledge about lipid metabolism in cancer from basic experiments can be transferred to develop strategies targeting this reprogramed metabolism.

There is currently a growing interest in diets and physical activity patterns that may be beneficial in preventing and treating breast cancer (BC). Mounting evidence indicates that indeed, the so-called Mediterranean diet (MedDiet) and regular physical activity likely both help reduce the risk of developing BC. For those who have already received a BC diagnosis, these interventions may decrease the risk of tumor recurrence after treatment and improve quality of life. Studies also show the potential of other dietary interventions, including fasting or modified fasting, calorie restriction, ketogenic diets, and vegan or plant-based diets, to enhance the efficacy of BC therapies. In this review article, we discuss the biological rationale for utilizing these dietary interventions and physical activity in BC prevention and treatment. We highlight published and ongoing clinical studies that have applied these lifestyle interventions to BC patients. This review offers valuable insights into the potential application of these dietary interventions and physical activity as complimentary therapies in BC management.