Marker For Cancer Progression Research Articles

Eosinophilic granulocytes as a potential prognostic marker for cancer progression and therapeutic response in malignant melanoma.

The importance of eosinophilic granulocytes in cancer has been widely discussed in recent years. The current study reviews the evidence on the role of eosinophilic granulocytes in melanoma as a prognostic marker for cancer progression and the efficacy of treatment with modern immune checkpoint inhibitors. A total of 33 human clinical studies were included in the review, with heterogeneous data due to differences in patients populations, study design and inclusion of small study groups. However, 28 of the 33 studies suggested that eosinophilic granulocytes could be used as a prognostic biomarker for outcome and/or potential response to systemic treatment and/or occurrence of adverse events in melanoma patients. Nevertheless, the exact role of eosinophils remains to be elucidated. Further prospective, larger and better controlled studies are warranted to clarify the significance of eosinophilic granulocytes in patients with melanoma, in more details.

Extra-nuclear TERT counteracts oxidative stress and promotes progression in papillary thyroid carcinoma

The reactivation of TERT is associated with poor outcome in papillary thyroid cancer (PTC). Extra-telomeric functions of TERT were reported, with a protective role against oxidative stress (OS). The aim of the present study was to explore the extra-nuclear TERT localization in PTC and its role in cancer progression.TERT nuclear export under OS were analyzed in K1 PTC cell line. We investigated the role of different TERT localizations using specific TERT constructs that limit its localization to the nucleus or to the mitochondria. The effect of SRC kinase inhibitor PP2, which reduces TERT nuclear export, was investigated as well. Moreover, TERT localization was analyzed in 39 PTC tissues and correlated with the genetic profile and the level of OS, DNA damage and apoptosis in the tumors and with the clinical characteristics of the patients.We demonstrated that TERT is exported from the nucleus in response to OS induced either from H2O2 or the BRAF inhibitor PLX4720. We proved that extra-nuclear TERT reduces mitochondrial OS and induces mitochondrial fragmentation. Moreover, limiting mitochondrial TERT localization reduced proliferation, migration, AKT phosphorylation and glycolysis and increased DNA damage and p21 expression. Finally, in PTC tissues the fraction of mitochondrial/nuclear TERT resulted inversely correlated with OS and p21 expression and associated with tumor persistence.In conclusion, our data indicate that extra-nuclear TERT is involved in reducing the effect of excessive OS, thus promoting cancer cell survival. Extra-nuclear TERT may thus represent a marker of cancer progression and a possible therapeutic target in PTC.

Abstract 847: Association of methylation-based stem cell divisions with lifetime cancer risk and cancer progression

Abstract Cancer initiation arises from the accumulation of somatic mutations acquired during stem cell mitotic events mediated by carcinogenic risk factors. On an ecological level, Tomasetti and Vogelstein (2015) demonstrated that lifetime risk of solid tumor cancer types were strongly correlated with total number of stem cell divisions estimated from tissue-specific cell lines. Recently, several mitotic clocks (MC) have been developed to estimate stem cell division rates (SCDR) based on whole-genome methylation arrays. Here, we compare estimated SCDR for several tissue types with tissue-specific cancer incidence and lifetime risk estimates. Furthermore, we assess the link between SCDR with cancer progression and survival. Array-based methylation data derived from normal adjacent tissue in TCGA was used to estimate SCDR for 15 cancer types. A Pearson correlation test was performed to assess the association between SCDR and cancer-specific incidence and lifetime risk for each cancer type overall and stratified by self-reported race (e.g. White and Black). SCDR was estimated in tumors from TCGA for 4 common cancers and subtypes: breast (BRCA), prostate (PRAD), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). A Spearman correlation test was used to identify potential trends between SCDR and pathological stage. Cox proportional hazard (PH) models adjusted for age at diagnosis and treatment status (e.g. surgery, radiation, etc.) were used to evaluate the association of time to death with SCDR terciles across different cancer stages. We observed a similar trend between SCDR and overall incidence (cor=0.61, p=0.01), aligning with earlier findings. Stratified-specific trends between cancer incidence and SCDR was consistent for both Black and White populations (cor=0.62 vs 0.66). Tumor analysis revealed a significant correlation between SCDR and pathological stage (e.g. stage 1, 2, and 3/4) for BRCA (p<0.001) and pathological stage (e.g. stage 2, 3 and 4) for PRAD (p<0.001), suggesting its potential as a marker of cancer progression. However, the correlation between LUAD, LUSC and pathological stage was insignificant. Based on Cox PH model, within stage III BRCA, SCDR significantly contributed to explaining variability in survival (p=0.04), emphasizing its potential prognostic value beyond cancer stage. Our study supports earlier findings applying methylation based SCDR estimates and shows that this association is consistent across racial groups. This implies that SCDR may act as a biological marker of a combination of various genetic and environmental risk factors underlying disease etiology. Further analyses will be extended to all cancers in TCGA. Lastly, we demonstrate that MC-based SCDR estimation has the potential to serve as a clinical tool to identify individuals at elevated risk of cancer initiation, track progression, and complement cancer stage for predicting survival. Citation Format: Yanning Wu, Cheryl Thompson, Fredrick Schumacher. Association of methylation-based stem cell divisions with lifetime cancer risk and cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 847.

Abstract 6358: Arming tumor-associated macrophages to inhibit cancer progression

Abstract Integrin αvβ3 is a marker of cancer progression in a range of epithelial cancers. In the 1990s, a humanized anti-αvβ3 antibody (Etaracizumab) was developed to target αvβ3+ cancer cells via NK cell-mediated cytotoxicity. While it demonstrated safety and some efficacy in clinical trials, our recent study of the immune microenvironment in αvβ3+ human epithelial tumors revealed increased tumor-associated macrophages (TAMs) but minimal NK cell accumulation. Accordingly, we re-engineered Etaracizumab to favor TAM engagement over NK cells and compared the efficacy of this antibody (ABT101) to that of Etaracizumab in various αvβ3+ epithelial cancer models. While ABT101 and Etaracizumab exhibited identical affinity for αvβ3, ABT 101 showed superior anti-tumor activity in vivo. Notably, depleting NK cells in mice had no impact on ABT101’s effectiveness, while macrophage depletion completely abolished its anti-tumor activity. Interestingly, tumors in mice treated with ABT101 displayed a significant increase in TAMs. Here we define an “antigen-effector cell matching” strategy that allows for maximal anti-tumor activity for various drug resistant epithelial cancers. ABT101 will enter clinical trials for patients with drug resistant lung cancer in the first quarter of 2024. Citation Format: Joshua P. Reddy, Ziqi Yu, Ryan M. Shepard, Tami Von Schalscha, Stephen J. McCormack, Sara M. Weis, David A. Cheresh, Hiromi I. Wettersten. Arming tumor-associated macrophages to inhibit cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6358.

A whole-food, plant-based randomized controlled trial in metastatic breast cancer: weight, cardiometabolic, and hormonal outcomes

PurposeBreast cancer treatment is associated with weight gain, and obesity and its related cardiometabolic and hormonal risk factors have been associated with poorer outcomes. Dietary intervention may address these risk factors, but limited research has been done in the setting of metastatic breast cancer requiring systemic therapy.MethodsWomen with metastatic breast cancer on stable treatment were randomized 2:1 to an 8-week intervention (n = 21) or control (n = 11). The intervention included weekly assessment visits and an ad libitum whole-food, plant-based (WFPB) diet with provided meals. Cardiometabolic, hormonal, and cancer markers were assessed at baseline, 4 weeks, and 8 weeks.ResultsWithin the intervention group, mean weight decreased by 6.6% (p < 0.01) after 8 weeks. Fasting insulin decreased from 16.8 uIU/L to 11.2 uIU/L (p < 0.01), concurrent with significantly reduced insulin resistance. Total cholesterol decreased from 193.6 mg/dL to 159 mg/dL (p < 0.01), and low-density lipoprotein (LDL) cholesterol decreased from 104.6 mg/dL to 82.2 mg/dL (p < 0.01). Total testosterone was unchanged, but free testosterone trended lower within the intervention group (p = 0.08) as sex hormone binding globulin increased from 74.3 nmol/L to 98.2 nmol/L (p < 0.01). There were no significant differences in cancer progression markers at week 8, although mean CA 15-3, CA 27.29, and CEA were lower in the intervention group (p = 0.53, p = 0.23, and p = 0.54, respectively) compared to control, when adjusted for baseline.ConclusionWFPB dietary changes during treatment for metastatic breast cancer are well tolerated and significantly improve weight, cardiometabolic and hormonal parameters. Longer studies are warranted to assess the durability of changes.Trial registration First registered at Clinicaltrials.gov (NCT03045289) on February 7, 2017.

3D-Nanostructured microfluidic device arranged in a herringbone pattern for the highly effective capture of HER2-Positive cancer-derived exosomes in urine

Exosomes in body fluids are important in liquid biopsy as they reflect the information of their originating cells. Thus, exosome analysis can provide valuable insights into diseases such as cancer. However, the low concentration of exosomes in body fluids is accompanied by background noise, making exosome analysis challenging. Here, a microfluidic chip in which three-dimensional nanostructures were arranged in a herringbone pattern (nanochip) that could efficiently capture specific exosomes was developed. Nanostructures were prepared by stacking silica nanoparticles to enhance the contact and interaction between the exosomes and structures, which were then arranged in a herringbone pattern to improve mass transfer through micromixing. To analyze exosomes derived from human epidermal growth factor receptor 2 (HER2, an important marker for cancer progression and patient survival)-positive cancer, anti-HER2 antibody was introduced into the nanostructures in the nanochip and approximately 97.7% of exosome capture efficiency was confirmed. The nanochip performed better than chips with a solid herringbone structure or without a structure (solid and flat chips). The feasibility of capturing multiple exosomes was demonstrated using both in vitro and in vivo samples by employing a dual nanochip configuration in which nanochips with different antibodies were interconnected in a series. This nanochip can effectively capture HER2-positive exosomes and has potential for multiple exosome isolations. Additionally, this chip can capture and detect various disease-related exosomes because various antibodies can be applied; this nanochip will be useful for exosome-based disease diagnosis and monitoring in liquid biopsies.

Up Regulation of Ezrin and Radixin with respect to Grade of Tumors in Breast Cancer Patients

Background: Breast cancer (BC) is one of the main causes of death among women in Iran. Biomarkers involved in promotion and progression of disease is very important in management and control of BC outcomes. In this research, we aim to estimate the expression levels of Ezrin and Radixin, as two important factors in morphogenesis, endocytosis, exocytosis, adherence, and migration of cells, in BC patients and their relationship with pathological factors.&#x0D; Methods: One hundred and thirteen BC patients were involved in this research. Relative expression of Ezrin and Radixin genes were estimated with quantitative real-time PCR. Pathological data include the histology, tumor size, grade, lymphovascular invasion and clinical TNM (Tumor, Node, and Metastasis) staging of patients were recorded based on the pathology report and their relationship with relative expression of Ezrin and Radixin were estimated.&#x0D; Result: According to result Ezrin were over expressed in tumor samples in comparison to adjacent normal tissue. There is a significant relationship between over expression of Ezrin and Radixin and grade of tumor and necrosis. Also there is a direct relationship between relative expression of Ezrin and Radixin expression.&#x0D; Conclusions: These data support the role of Ezrin and Radixin in the biology of breast cancer and additional studies needed that determine the Ezrin and Radixin associated with phenotype and may validate them as markers of cancer progression and as a potential target for cancer therapy.

MTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers

BackgroundMammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers.MethodsWe analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5–7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry.ResultsSirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression.ConclusionOverall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression.Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.

Systemic inflammation response index and aggregate inflammation systemic index in male and female cancers: Implication for gender based immunotherapy

&lt;b&gt;Background:&lt;/b&gt; Several blood cell ratios have emerged as easy and minimally evasive inflammatory markers of cancer progression and management. Systemic inflammation response index (SIRI) and aggregate inflammation systemic index (AISI), which are reliable indicators of inflammation because they are calculated using more than two immune cells, have not been widely studied. The present study is particularly important in delineating gender-based cancers and to suggest inflammation based therapy.&lt;br /&gt; &lt;b&gt;Methods: &lt;/b&gt;SIRI and AISI were calculated from differential white blood cell counts using automatic hematology analyzer in 50 cervical patients, 50 prostate cancer patients and 61 corresponding controls.&lt;br /&gt; &lt;b&gt;Results&lt;/b&gt;: Mean values of SIRI and AISI were significantly raised in cervical cancer patients and prostate cancer patients compared with corresponding control. The mean white blood cell and neutrophil counts were significantly raised while SIRI, monocyte counts and AISI were significantly reduced in prostate cancer patients compared with cervical cancer patients.&lt;br /&gt; &lt;b&gt;Conclusions&lt;/b&gt;: This study suggests that inflammation is a phenomenon in cervical- and prostate- cancer patients but the impact of inflammation might be more in cervical cancer patients, suggesting that sex hormones might limit the efficacy of broad spectrum single cancer immunotherapy for both sexes.

Role of the gut microbiota in hematologic cancer.

Hematologic neoplasms represent 6.5% of all cancers worldwide. They are characterized by the uncontrolled growth of hematopoietic and lymphoid cells and a decreased immune system efficacy. Pathological conditions in hematologic cancer could disrupt the balance of the gut microbiota, potentially promoting the proliferation of opportunistic pathogens. In this review, we highlight studies that analyzed and described the role of gut microbiota in different types of hematologic diseases. For instance, myeloma is often associated with Pseudomonas aeruginosa and Clostridium leptum, while in leukemias, Streptococcus is the most common genus, and Lachnospiraceae and Ruminococcaceae are less prevalent. Lymphoma exhibits a moderate reduction in microbiota diversity. Moreover, certain factors such as delivery mode, diet, and other environmental factors can alter the diversity of the microbiota, leading to dysbiosis. This dysbiosis may inhibit the immune response and increase susceptibility to cancer. A comprehensive analysis of microbiota-cancer interactions may be useful for disease management and provide valuable information on host-microbiota dynamics, as well as the possible use of microbiota as a distinguishable marker for cancer progression.

Telomere maintenance genes-derived prognosis signature characterizes immune landscape and predicts prognosis of head and neck squamous cell carcinoma.

Telomere dysfunction has been identified as a biological marker of cancer progression in several types of cancer, including Head and Neck Squamous Cell Carcinoma (HNSCC). This study aimed to characterize the telomere maintenance genes (TMG)-related signature in prognosis and treatment response in HNSCC. The transcriptome and clinical data of HNSCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases, respectively. Non-negative matrix factorization (NMF) was used to identify molecular subtypes derived from TMG. Gene set enrichment analysis (GSEA) was performed to analyze the differentially expressed pathways between subtypes, and a risk score model derived from TMG was established. Kaplan-Meier survival analysis was used to evaluate inter-group prognostic features, and the correlation between TMG-derived molecular subtypes and risk score model with immune infiltration, immunotherapy, and chemosensitivity was assessed. Two HNSCC subtypes were identified based on 59 TMG-related genes, which exhibit significant heterogeneity in prognosis, immune cell infiltration, and treatment response. Additionally, a TMG-derived risk signature containing 9 genes was developed to assess the prognosis of HNSCC patients. The signature had significant predictive ability for HNSCC prognosis and was significantly correlated with immune cell infiltration and immunotherapy response. A nomogram integrating the risk signature, N stage and radiotherapy was constructed to predict 1-, 3-, and 5-year overall survival (OS) of HNSCC patients, which had better performance than other prognostic models and included TMG-derived risk score, radiotherapy, and N stage. This study identified TMG-derived molecular subtypes in HNSCC and developed a novel prognostic score model, highlighting the potential value of TMG in HNSCC prognosis and immunotherapy.

E-Cadherin Expression Varies Depending on the Location within the Primary Tumor and Is Higher in Colorectal Cancer with Lymphoid Follicles.

Reliable indicators of cancer advancement have actively been sought recently. The detection of colorectal cancer progression markers is essential in improving diagnostic and therapeutic protocols. The aim of the study was to investigate the profile of E-cadherin expression in colorectal cancer tissue depending on the TNM staging and its correlation with several clinical and histopathological features. The study included 55 colorectal cancer patients admitted to the surgical ward for elective surgery. Tissue samples were obtained from resected specimens. Different distributions of E-cadherin expression within tumors were observed; the highest percentage of positive E-cadherin expression was found in the invasive front and in the tumor center. Additionally, the different cellular distribution of E-cadherin expression was noticed; weak membranous E-cadherin expression was the highest in the invasive front and in the budding sites, but a strong membranous pattern was most frequent in the tumor center. Various distributions of E-cadherin expression depending on cancer progression were also found; E-cadherin expression in node-positive patients was lower in the tumor center and in the tumor invasive front, whereas, in patients with distant metastases, the expression of E-Cadherin was lower in the budding sites. In patients with higher TNM stages, E-cadherin expression was lower within the tumor (in the budding sites, tumor center, and invasive front). In tumors with lymphoid follicles, E-cadherin expression was higher in all localizations within the primary tumor. E-cadherin expression in the tumor center was also lower in tumors with some higher tumor budding parameters (areas of poorly differentiated components and poorly differentiated clusters). E-cadherin expression was found to be lower at the tumor center in younger individuals, at the budding sites in men, and at the surrounding lymph nodes in rectal tumors. Low E-cadherin expression appears to be a reliable indicator of higher cancer staging and progression. When assessing the advancement of cancer, apart from the TNM classification, it is beneficial to also consider the expression of E-cadherin. High tumor budding, the poverty of lymphoid follicles, and low E-cadherin expression analyzed simultaneously may contribute to a reliable assessment of colorectal cancer staging. These three histopathological features complement each other, and their investigation, together with conventional tumor staging and grading, may be very helpful in predicting the prognosis of colorectal cancer patients and qualifying them for the best treatment. The role of E-cadherin in the diagnosis and treatment of colorectal cancer, as a part of a personalized medicine strategy, still requires comprehensive, prospective clinical evaluations to precisely target the optimal therapies for the right patients at the right time.

AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK.

PNCK, or CAMK1b, is an understudied kinase of the calcium-calmodulin dependent kinase family which recently has been identified as a marker of cancer progression and survival in several large-scale multi-omics studies. The biology of PNCK and its relation to oncogenesis has also begun to be elucidated, with data suggesting various roles in DNA damage response, cell cycle control, apoptosis and HIF-1-alpha related pathways. To further explore PNCK as a clinical target, potent small-molecule molecular probes must be developed. Currently, there are no targeted small molecule inhibitors in pre-clinical or clinical studies for the CAMK family. Additionally, there exists no experimentally derived crystal structure for PNCK. We herein report a three-pronged chemical probe discovery campaign which utilized homology modeling, machine learning, virtual screening and molecular dynamics to identify small molecules with low-micromolar potency against PNCK activity from commercially available compound libraries. We report the discovery of a hit-series for the first targeted effort towards discovering PNCK inhibitors that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes.

Abstract 5387: Discovery of plasma protein biomarkers associated with overall survival in R/R DLBCL patients treated with loncastuximab tesirine

Abstract Plasma proteomics is a non-invasive source of potential biomarkers associated with cancer treatment outcomes, including disease progression and overall survival (OS). Loncastuximab tesirine (lonca) is an antibody-drug conjugate, composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin, for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Here, we investigated the association of plasma protein biomarkers with OS of R/R DLBCL patients prior to treatment with lonca (phase 2 trial, NCT3589469, LOTIS-2). Abundances of 888 plasma proteins, including inflammation, cancer and DNA repair associated markers, were measured for 69 patients with R/R DLBCL from plasma samples collected at baseline. Protein markers predictive of OS were selected using a L1 regularized Cox proportional hazards model (CoxPH) incorporating survival time and censoring status. Protein modules associated with OS were discovered by performing principal component analysis (PCA) on scaled protein abundances. Gene Set Enrichment Analysis (GSEA) was performed using Molecular Signatures Database (MSigDB) sets. We initially applied a regularized COX proportional hazards model to our proteomics dataset to identify proteins associated with OS, which revealed 5 protein markers (associated with decreased survival = REG3A, LAP3; associated with increased survival = NPTXR, C1QTNF1, FLT3) which stratified patients into distinct survival groups (p = 2.3e-4). As a complement to this approach and to extend our biological understanding of this cohort, we then applied PCA to the proteomics data to reveal underlying protein modules associated with survival. Our analysis identified principal component 3 (PC3) to have the strongest association to OS (rho= -0.63, FDR = 8.7e-07); with its top loadings consisting of known markers of cancer progression (top 3 proteins: SIGLEC10, IL6, TNFRSF6B). GSEA on PC3 loadings identified 68 significantly enriched gene sets (FDR &amp;lt; 5%). Gene sets reflective of changes in immune activation, increased cytokine activity and interleukin mediated activation (IL6, IL10) were negatively associated with OS, including activation of the following Hallmark pathways: IL6/JAK/STAT3 signaling and inflammatory response pathways.Overall, our results identify proteomics markers associated with DLBCL survival upon treatment with lonca, highlighting the potential of plasma proteins as a source of relevant biomarkers pending additional validation. [FV and VC contributed equally to this work] Citation Format: Francesco Vallania, Victoria Cheung, Anupriya Tripathi, Maggie Louie, Thomas Snyder, Jimmy Lin, Karin Havenith, Yajuan Qin, Serafino Pantano, Jens Wuerthner, Patrick H. van Berkel. Discovery of plasma protein biomarkers associated with overall survival in R/R DLBCL patients treated with loncastuximab tesirine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5387.

Abstract P4-07-31: A whole food, plant-based (WFPB) dietary intervention to improve cardiometabolic and cancer-related outcomes in women with breast cancer

Abstract Background: With dramatically rising obesity rates in the US, obesity at breast cancer diagnosis is common; further compounding the problem is that breast cancer treatment often results in additional weight gain. Among women undergoing breast cancer treatment, both obesity at diagnosis and post-diagnosis weight gain are associated with increased all-cause mortality and increased breast cancer mortality. We tested a WFPB dietary intervention in metastatic breast cancer patients to improve cardiometabolic and cancer-related outcomes, as it has been shown to reduce weight and improves cardiometabolic health in overweight and obese individuals. Methods: Women with stage 4 breast cancer receiving treatment were randomized 2:1 into 2 arms: 1) a WFPB diet (N=21) or 2) usual diet (N=11) for 8 weeks with assessments at baseline, 4, and 8 weeks. Our WFPB diet consisted of an ad libitum whole food, plant-based diet; 3 meals/day were provided to WFPB subjects, which included fruits, vegetables, whole grains, nuts and seeds, and excluded meat, dairy, eggs, and added oils/solid fats. WFPB subjects received weekly education regarding diet. Subjects in the usual care group were asked to continue their usual diet for the next 8 weeks. Outcomes include cardiometabolic risk factors, related sex hormones, and cancer progression markers. Effects of the WFPB diet on the outcomes were assessed by comparing marginal means by arm estimated at 8 weeks from the analysis of covariance model controlling for the baseline value. Results: Of the 32 subjects randomized, 30 subjects (20 WFPB and 10 usual care) completed all 3 assessments. Reductions in weight, BMI, total cholesterol, and LDL cholesterol were statistically significant as well as clinically meaningful, both within the WFPB group and between the groups. In the WFPB group, subjects lost a mean of 6.2% of their body weight versus 0.7% body weight loss in the control group (p&amp;lt; 0.01). LDL cholesterol was reduced by a mean of 20.0% in the WFPB subjects versus a 10.6% increase in control subjects (p&amp;lt; 0.01). Reductions in insulin and HOMA-IR, a measure of insulin sensitivity, were statistically significant within the WFPB group and trended towards significance between the groups. Sex hormone binding globulin (SHBG) levels increased significantly both within the WFPB group and between groups. There was a significant decrease in both IGF-1 and free testosterone within the WFPB group from baseline to week 8. Conclusions: Our WFPB intervention resulted in improvements in several cardiometabolic and hormonal markers. The intentional weight loss, which was clinically large given the duration of the trial, was accompanied by reduced cholesterol, insulin resistance, free testosterone, and IGF-1. Given the moderate to large effect sizes noted, further study is warranted to evaluate the sustainability of benefits over time and to assess their potential impact on cancer-related outcomes. Table 1: Cardiometabolic and Cancer-Related Outcomes Citation Format: Erin Campbell, Thomas Campbell, Eva Culakova, Nellie Wixom, Joseph Guido, Lisa Blanchard, James Fetten, Michelle Janelsins, Karen Mustian, Luke Peppone. A whole food, plant-based (WFPB) dietary intervention to improve cardiometabolic and cancer-related outcomes in women with breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-31.

Identification of angiogenesis-related subtypes, the development of prognostic models, and the landscape of tumor microenvironment infiltration in colorectal cancer.

Background: Angiogenesis is one of the most prominent markers of cancer progression and contributes to tumor metastasis and prognosis. Anti-angiogenic drugs have proven effective in treating metastatic colorectal cancer. However, there is some uncertainty regarding the potential role of angiogenesis-related genes in the tumor microenvironment. Methods: We analyzed 1,214 colorectal cancer samples to identify alterations in angiogenesis-related genes (ARGs), and then correlated angiogenesis with clinical features, prognosis, and TME. The ARGs expression profiles in colorectal cancer were analyzed using three computational methods (CIBERSORT, ssGSEA, and MCPcounter) and provided a systematic immune landscape. Patients with CRC were classified into two subtypes based on consensus clustering analysis of angiogenesis-related genes. The revealed differentially expressed genes between the two subtypes were used to create and validate ARGscore prognostic models. In addition, we collected eight colorectal cancer patient specimens and performed RT-qPCR to validate the signature gene expression. Results: We assessed the expression patterns of ARGs in colorectal cancer. We identified two molecular subtypes and confirmed that the expression of ARGs was associated with prognosis and TME characteristics. Based on differentially expressed genes between subtypes, we constructed ARGscore and evaluated their predictive power for the survival of colorectal cancer patients. We also developed an accurate nomogram to make the ARGscore more clinically useful. In addition, ARGscore was significantly correlated with microsatellite instability, cancer stem cells, and chemotherapeutic drug sensitivity. Patients with ARGscore-low characterized by immune activation and microsatellite instability high had a better prognosis. Conclusion: ARGs expression influenced the prognosis, clinicopathological features, and tumor stromal immune microenvironment in colorectal cancer. We developed a new risk model, ARGscore, for the treatment and prognosis of CRC patients and validated its promising predictive power. These findings will enable us to understand colorectal cancer better, assess prognoses, and develop more effective treatment options.

Voltage-dependent inhibition of thermo-TRPV channels by intracellular spermine.

The Vanilloid TRP (TRPV1-4) subfamily of channels is involved in thermoregulation, osmoregulation, itch and pain perception, immune response and (neuro)inflammation, and tight control of channel activity is required for perception of pain and noxious stimuli. TRPV1, 2, 4 have been shown to be overexpressed in various cancer cell types and suggested to serve as a marker of cancer progression and, in some cases, as an anti-cancer drug target. The polyamines (PAs) putrescine, spermidine and spermine, are present in sub-millimolar concentrations in the cytoplasm of virtually all cells and in the extracellular fluid. Intracellular PA levels decrease with age, while pathological alterations of PA levels affect cognitive functions and have been linked to brain ageing and degeneration, as well as to cancer. We have discovered a previously unrecognized physiological modulation of human TRPV1, 3 and 4 by the endogenous intracellular polyamine spermine. As in inward rectifier K channels, currents are blocked in a strongly voltage-dependent manner, but, as in cyclic nucleotide-gated channels, the block is substantially relieved at more positive voltages. Consistent with block relief resulting from spermine permeation, there is much weaker relief of block by the analog 1-naphthyl-acetyl spermine, with a bulky aromatic group at one end of the molecule. A kinetic model of inhibition suggests two independent spermine binding sites with different affinities as well as significantly different degrees of PA permeability in TRPV1, 3, and 4. Since block, relief, and permeation occur over the physiological voltage range of action potentials and PA concentrations, voltage-dependent PA block may be a potent modulator of TRPV-dependent excitability in multiple cell types, and at least some TRPV channels may contribute to polyamine transport. Thermo-TRPV structural insights and available literature also hint at a common mechanism of PA block of different TRP channel sub-families.

The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression.

Cancer is a multifactorial, complex disease exhibiting extraordinary phenotypic plasticity and diversity. One of the greatest challenges in cancer treatment is intratumoral heterogeneity, which obstructs the efficient eradication of the tumor. Tumor heterogeneity is often associated with the presence of cancer stem cells (CSCs), a cancer cell sub-population possessing a panel of stem-like properties, such as a self-renewal ability and multipotency potential. CSCs are associated with enhanced chemoresistance due to the enhanced efflux of chemotherapeutic agents and the existence of powerful antioxidant and DNA damage repair mechanisms. The distinctive characteristics of CSCs make them ideal targets for clinical therapeutic approaches, and the identification of efficient and specific CSCs biomarkers is of utmost importance. Aldehyde dehydrogenases (ALDHs) comprise a wide superfamily of metabolic enzymes that, over the last years, have gained increasing attention due to their association with stem-related features in a wide panel of hematopoietic malignancies and solid cancers. Aldehyde dehydrogenase 1B1 (ALDH1B1) is an isoform that has been characterized as a marker of colon cancer progression, while various studies suggest its importance in additional malignancies. Here, we review the basic concepts related to CSCs and discuss the potential role of ALDH1B1 in cancer development and its contribution to the CSC phenotype.

Circulating tumor cells and circulating tumor DNA in breast cancer diagnosis and monitoring.

Liquid biopsy, including both circulating tumor cells and circulating tumor DNA, is becoming more popular as a diagnostic tool in the clinical management of breast cancer. Elevated concentrations of these biomarkers during cancer treatment may be used as markers for cancer progression as well as to understand the mechanisms underlying metastasis and treatment resistance. Thus, these circulating markers serve as tools for cancer assessing and monitoring through a simple, non-invasive blood draw. However, despite several study results currently noting a potential clinical impact of ctDNA mutation tracking, the method is not used clinically in cancer diagnosis among patients and more studies are required to confirm it. This review focuses on understanding circulating tumor biomarkers, especially in breast cancer.

Editors' Selections from Relevant Scientific Publications

Editors' Selections from Relevant Scientific Publications