Disease-free Survival In Cancer Patients Research Articles

Tetraploidization Increases the Motility and Invasiveness of Cancer Cells.

Polyploidy and metastasis are associated with a low probability of disease-free survival in cancer patients. Polyploid cells are known to facilitate tumorigenesis. However, few data associate polyploidization with metastasis. Here, by generating and using diploid (2n) and tetraploid (4n) clones from malignant fibrous histiocytoma (MFH) and colon carcinoma (RKO), we demonstrate the migration and invasion advantage of tetraploid cells in vitro using several assays, including the wound healing, the OrisTM two-dimensional cell migration, single-cell migration tracking by video microscopy, the Boyden chamber, and the xCELLigence RTCA real-time cell migration. Motility advantage was observed despite tetraploid cell proliferation weakness. We could also demonstrate preferential metastatic potential in vivo for the tetraploid clone using the tail vein injection in mice and tracking metastatic tumors in the lung. Using the Mitelman Database of Chromosome Aberrations in Cancer, we found an accumulation of polyploid karyotypes in metastatic tumors compared to primary ones. This work reveals the clinical relevance of the polyploid subpopulation and the strategic need to highlight polyploidy in preclinical studies as a therapeutic target for metastasis.

Prognostic and clinicopathological value of m6A regulators in human cancers: a meta-analysis.

N6-methyladenosine (m6A) is the most abundant epigenetic modification. Although the dysregulation of m6A regulators has been associated with cancer progression in several studies, its relationship with cancer prognosis and clinicopathology is still controversial. Therefore, we evaluated the prognostic and clinicopathological value of m6A regulators in cancers by performing a comprehensive meta-analysis. The PubMed, Cochrane Library, Web of Science, and Embase databases were searched up to April 2022. Hazard ratios were used to analyze the association between m6A with prognosis. We also analyze the relationship between m6A and clinicopathology using odds ratios. METTL3 overexpression predicted poor overall survival and disease-free survival in cancer patients (p < 0.001) such as gastric cancer (p < 0.001), esophageal squamous cell carcinoma (p < 0.001), oral squamous cell carcinoma (p = 0.002) and so on. Additionally, METTL3 overexpression was associated with poor pT stage (p < 0.001), pN stage (p < 0.001), TNM stage (p < 0.001), tumor size >5 cm (p < 0.001) and vascular invasion (p = 0.024). Conversely, METTL14 overexpression was positively associated with better OS (p < 0.001), negatively with poor pT stage (p = 0.001), pM stage (p = 0.002), pN stage (p = 0.011) and TNM stage (p < 0.001). Moreover, KIAA1429 overexpression was associated with poor OS (p = 0.001). YTHDF1 overexpression was also associated with advanced pM stage (p < 0.001) and tumor size >5 cm (p < 0.001). However, ALKBH5 overexpression was negatively associated with vascular invasion (p = 0.032). High expression of METTL3 predicted poor outcome. In contrast, high expression of METTL14 was associated with better outcome. Thus, we suggest that among all the m6A regulators, METTL3 and METTL14 could be potential prognostic markers in cancers.

Prognostic value of hemoglobin-to-red cell distribution width ratio in cancer: a systematic review and meta-analysis.

Background: The hemoglobin-to-red cell distribution width ratio (HRR) has emerged as a novel integrative biomarker predictive of overall and disease-free survival in cancer patients. This study aimed to investigate the prognostic significance of HRR in the cancer population. Methods: A literature search was performed in PubMed/MEDLINE from inception to 1July 2021, to collect studies assessing the prognostic value of HRR in cancer patients. The primary and secondary end points were all-cause mortality and occurrence of disease progression or relapse, respectively. A meta-analytic approach was employed to estimate the pooled hazard ratio with 95% CI by fitting random-effects models. Results: A total of 11 retrospective cohort studies representing 2985 cancer patients were included. Compared with patients with high HRR, patients with low HRR had a twofold risk of all-cause mortality (hazard ratio: 2.29; 95% CI: 1.76-2.98; p<0.0001). There was substantial heterogeneity in the association of HRR with mortality across the studies (I2: 66.8%; 95% CI: 35.3-82.9%; p=0.0014). Similarly, low HRR was associated with a twofold risk of disease progression or relapse (hazard ratio: 2.19; 95% CI: 1.74-2.76; p<0.0001). No significant heterogeneity was observed (I2: 16.8%; 95% CI: 0.0-60.7%; p=0.30). Conclusion: Low HRR was associated with mortality and disease progression or relapse in patients with cancer. Further studies are required to standardize the HRR cutoff value and investigate whether HRR can be incorporated into risk assessment models for predicting adverse prognosis in cancer patients.

High expression of S100A8 and S100A9 is associated with poor disease-free survival in patients with cancer: a systematic review and meta-analysis.

BackgroundThe expression of S100A8 and S100A9 is found to be related with the survival of cancer patients, but the results and information regarding their prognostic significance are inconsistent in literature. This study, therefore, aimed to perform a comprehensive meta-analysis and determine the prognostic significance of S100A8 and S100A9 expression in patients with cancer.MethodsData were collected by performing a literature search on the PubMed, Cochrane library, and Scopus databases. Pooled hazard ratio (HR) with confidence interval (CI) was calculated to assess the correlation between S100A8 and S100A9 expression and survival in patients with cancer.ResultsIn total, 5 studies that enrolled 735 cancer patients were included in the meta-analysis. The pooled HR concerning S100A8 and S100A9 expression was 1.98 (95% CI: 1.20–3.29, P=0.008) for disease-free survival (DFS), indicating an association between high expression of S100A8 and S100A9 and poor DFS in cancer patients. However, the expression of S100A8 and S100A9 was not significantly correlated with disease-specific survival (HR 1.71, 95% CI: 0.86–3.40, P=0.128).DiscussionThe current meta-analysis revealed that S100A8 and S100A9 expression may be a potential prognosticator of DFS in cancer patients. The present systematic review is the first to investigate the survival outcomes of cancer patients with S100A8 and S100A9 expression.

The role of FOXD2-AS1 in cancer: a comprehensive study based on data mining and published articles.

Background and aims: Long non-coding RNA (lncRNA) FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) is aberrantly expressed in various cancers and associated with cancer progression. A comprehensive meta-analysis was performed based on published literature and data in the Gene Expression Omnibus database, and then the Cancer Genome Atlas (TCGA) dataset was used to assess the clinicopathological and prognostic value of FOXD2-AS1 in cancer patients.Methods: Gene Expression Omnibus databases of microarray data and published articles were used for meta-analysis, and TCGA dataset was also explored using the GEPIA analysis program. Hazard ratios (HRs) and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the role of FOXD2-AS1 in cancers.Results: This meta-analysis included 21 studies with 2391 patients and 25 GEO datasets with 3311 patients. The pooled HRs suggested that highly expressed FOXD2-AS1 expression was correlated with poor overall survival (OS) and disease-free survival (DFS). Similar results were obtained by analysis of TCGA data for 9502 patients. The pooled results also indicated that FOXD2-AS1 expression was associated with bigger tumor size and advanced TNM stage, but was not related to age, gender, differentiation and lymph node metastasis.Conclusion: The present study demonstrated that FOXD2-AS1 is closely related to tumor size and TNM stage. Additionally, increased FOXD2-AS1 was a risk factor of OS and DFS in cancer patients, suggesting FOXD2-AS1 may be a potential biomarker in human cancers.

Abstract 2413: Ferroptosis plays an important role in the radiotherapy-induced tumor suppression and radioresistance

Abstract Introduction: Radiotherapy (RT) is widely used to treat cancers, but radioresistance remains a major factor in the failure of RT. RT generates reactive oxygen species (ROS) through the radiolysis of cellular water and the stimulation of oxidase, causing cellular damage. Ferroptosis is a regulated cell death induced by iron-dependent peroxidation of phospholipids containing polyunsaturated fatty acids (PUFA-PLs), which is morphologically and mechanistically distinct from apoptosis. There are several core regulators in ferroptosis pathway. SLC7A11 and GPX4 play a role in inhibiting ferroptosis, whereas ACSL4, as an essential lipid metabolism enzyme, promotes ferroptosis by regulating the biosynthesis of PUFA-PLs. Ferroptosis can be induced by either class 1 ferroptosis inducers (FINs) that inhibit SLC7A11 or class 2/3 FINs that inhibit or deplete GPX4. Our study aims to determine the role and mechanisms by which ferroptosis contributes to RT-induced cell death and tumor suppression and to evaluate therapeutic potential of FINs as robust radiosensitizers. Methods: Ferroptosis markers such as lipid peroxidation or PTGS2 expression was evaluated by flow cytometry, q-PCR or transmission electron microscopy (TEM). Mechanisms were analyzed by western blot and CRISPR-Cas9. Patient derived xenografts (PDX) co-treated with RT and FINs were employed to access the combination effectiveness. Samples were collected from patients before and after RT and ferroptosis marker 4-HNE was correlated with prognosis of patients. Results: RT induced lipid peroxidation and PTGS2 expression in a variety of cancer types and TEM revealed that cancer cells after RT exhibited shrunken mitochondria with enhanced membrane density, a morphologic feature of ferroptosis. Treatment with ferroptosis inhibitor ferrostatin-1 significantly restored cell survival that had been reduced by exposure to RT, suggesting ferroptosis represents an important part of the RT-induced cell death response. Mechanistically, RT up-regulated the expression of ACSL4, together with RT-generated ROS, to promote lipid peroxidation and ferroptosis. RT also induced the expression of ferroptosis negative regulators, including SLC7A11 and GPX4, leading to radioresistance. In preclinical model, ferroptosis inhibitor liproxstatin-1 partially abolished the RT-induced tumor suppression in H460 xenografts, and FINs (e.g. sulfasalazine) treatment exhibited a significant radiosensitization in A549 xenografts or radioresistant lung cancer patient-derived xenografts (PDXs). In clinical analysis, we revealed very weak 4-HNE levels in all tumor samples before RT, but RT increased 4-HNE levels moderately or strongly in all tumor samples. Importantly, the 4-HNE levels were positively correlated with RT response and disease-free survival in cancer patients. Conclusions: Our study reveals a previously unrecognized link between RT and ferroptosis, and demonstrates that FINs as a radiosensitizer reverse ferroptosis-mediated radioresistance, and proposes a novel combination therapeutic strategy for cancers, providing an effective approach to overcome radioresistance and facilitating us to initiate follow-up clinical trials to further explore the therapeutic potential of FINs combined with RT in cancer patients. Citation Format: Guang Lei, Yilei Zhang, Pranavi Koppula, Xiaoguang Liu, Steven Hsesheng Lin, Zhongxing Liao, Hui Wang, Boyi Gan. Ferroptosis plays an important role in the radiotherapy-induced tumor suppression and radioresistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2413.

The Gα-interacting vesicle-associated protein interacts with and promotes cell surface localization of GRP78 during endoplasmic reticulum stress.

Cell surface translocation of the chaperone glucose-regulated protein 78kDa (GRP78) is a key event that promotes cancer cell survival during endoplasmic reticulum (ER) stress. Here, we identify Gα-interacting vesicle-associated protein (GIV) - an enhancer of prosurvival signaling during ER stress - as a binding partner of GRP78. We show that GIV and GRP78 interact in an ER stress-dependent manner through their respective carboxyl terminal domains and that GIV aids in the localization of GRP78 to the plasma membrane. Kaplan-Meier analysis of disease-free survival in cancer patients shows poor prognosis for patients with high expression of both GIV and GRP78, further suggesting a vital role for these two proteins in enhancing cancer cell viability.

Prognostic value of lncRNA FEZF1 antisense RNA 1 over-expression in oncologic outcomes of patients with solid tumors

Background:FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1), as a novel lncRNA, was reported to be up-regulated in various cancers and involved in tumor progression. This study systematically assessed the prognostic value of FEZF1-AS1 in solid tumors.Methods:Web of Science, PubMed, EMBASE, Chinese National Knowledge Infrastructure, and Wanfang databases were searched for eligible studies that evaluated the prognostic role of FEZF1-AS1 expression in cancer patients. Pooled hazard ratios (HRs) and combined odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated. The meta-analysis was conducted using Stata/SE 14.1.Results:Fifteen original studies involving 1378 patients were enrolled. Pooled results showed that increased expression of FEZF1-AS1 significantly correlated with shorter overall survival (OS) in cancer patients (HR 2.04, 95% CI 1.60–2.47), and also shorter disease-free survival (DFS) (HR 2.08, 95% CI 1.27–2.89). Additionally, the combined ORs indicated that increased FEZF1-AS1 expression was significantly associated with lymph node metastasis (OR 3.35, 95% CI 1.98–5.67), distant metastasis (OR 3.10, 95% CI 1.86–5.15), poor tumor differentiation (OR 2.90, 95% CI 1.45–5.80), high depth of tumor invasion (OR 2.72, 95% CI 1.36–5.43), and advanced clinical stage (OR 2.76, 95% CI 1.75–4.35). Expression analysis using the Gene Expression Profiling Interactive Analysis database indicated that the expression of FEZF1-AS1 was higher in tumor tissues than that in the corresponding normal tissues. The results of survival analysis revealed that increased FEZF1-AS1 expression was correlated with poor OS and DFS in cancer patients.Conclusions:LncRNA FEZF1-AS1 may serve as a valuable prognostic biomarker for clinical outcomes in various solid tumors.

Prognostic significance of the ratio of fibrinogen and albumin in human malignancies: a meta-analysis.

Background and aim: Serum fibrinogen and albumin are two important factors in systemic inflammation and these two factors are related to tumor progression. This study aimed to comprehensively reveal the prognostic value of the ratio of fibrinogen and albumin in malignant tumors.Methods: We systematically searched relevant studies in PubMed, Web of Science and Embase up to November 21, 2018. Hazard ratios (HRs) or odds ratio (ORs) for overall survival (OS)/disease-free survival (DFS), as well as relevant clinical data, were collected for analysis; all data analyses were performed by using STATA/SE 14.Results: Twelve cohort studies were included in this meta-analysis, with a total of 5,088 cases including 9 different kinds of tumors recruited. The pooled results showed that high albumin/fibrinogen ratio (FAR) and low fibrinogen/albumin ratio (AFR) were significantly associated with poor OS (HR=1.50, 95% CI: 1.30–1.70). Subgroup analyses for OS were also performed based on the disease type, detection method, follow-up time and treatment. Similarly, high FAR or low AFR indicated a worse DFS in cancer patients (HR=1.86; 95% CI: 1.41–2.31). In addition, high FAR or low AFR was statistically significant in relation to deeper tumor infiltration (OR=2.81, 95%CI: 1.67–4.72), positive lymph node metastasis (OR=1.57, 95%CI: 1.23–2.02) and distant metastasis (OR=2.30, 95% CI: 1.36–3.89) as well as advanced clinical stage (OR=2.02, 95% CI: 1.17–3.47).Conclusions: The ratio of fibrinogen and albumin could act as a promising prognostic marker in human malignant tumors. It might assist physicians to select optimal treatments by identifying the current status of the patient. Future multicenter clinical trials are needed to validate its applications.

PSMA-Directed Biologically-Guided Radiation Therapy of Castration-Sensitive Oligometastatic Prostate Cancer Patients

Local ablative treatment to oligometastatic (OM) patients can result in long term disease-free survival in cancer patients. The importance of consolidating all tumors in prostate cancer in the modern era is unknown. Stereotactic ablative radiation (SABR) is highly focused, high-dose radiation, but further dose escalation is still limited by target motion, localization uncertainties and difficultly irradiating multiple metastases simultaneously. Biology-guided radiotherapy (BgRT) is currently being developed to utilize PET emission data to guide radiotherapy delivery in real-time and to multiple targets. With this modality, the PET signals act as a biological fiducial that inherently tracks target motion and treatment setup uncertainties. Prostate membrane specific antigen (PSMA) is a cell surface protein that is overexpressed preferentially in prostate cancer and radiolabeled-ligands have been used for unprecedented molecular imaging in prostate cancer. Here we report on a pilot study examining PSMA-directed BgRT using a cohort from our Phase II randomized trial of SABR to men with recurrent low volume (1-3 metastases) metastatic hormone sensitive prostate cancer (HSPC) who have been imaged with PSMA PET-CT. Patients are randomized 2:1 to SABR:observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. All men treated with SABR were imaged with PSMA PET-CT at day 1 prior to SABR and day 180 from randomization. Four patients from this trial were used for a proof-of-concept study to compare conventionally planned SABR treatments versus BgRT treatments generated from a prototype treatment planning system (TPS). BgRT treatment plan prescriptions were duplicated from the conventional SABR treatment plans and the dose constraints for organs-at-risk (OARs) followed AAPM TG101 guidelines. No additional dose shaping structures were used for the BgRT plans. All patients had one metastatic site (n= 2 node & n= 2 bone) with an average PTV of 5.1 cc (range = 1.8-9.5 cc). All four BgRT plans met pre-specified planning objectives and were qualitatively acceptable even without the use of optimization structures. The BgRT plans displayed better PTV coverage, V95=96.9±2% versus V95=95.6%±1 for conventional SABR planning, were more heterogeneous [average Dmax of the prescription dose was 149% (range = 137-164%) for BgRT versus 123% (112-131%) for the conventional SABR] and gave more dose on average [Dmean 123% (range = 117-127%) for BgRT versus 112% (range = 109-116%) for conventional SABR] but had similar and in many cases better avoidance of OARs. This is a pilot BgRT planning study from the first randomized Phase II study evaluating the safety and efficacy of SABR in OM HSPC who have been imaged with PSMA PET-CT. Our study suggests comparable treatment plans between conventional and BgRT planned SABR and demonstrates the feasibility of PSMA-directed BgRT-guided SABR for OM HSPC.

Abstract 1543: Wogonin suppresses the production of breast cancer-derived osteolytic factors

Abstract Breast cancer is the most frequent cancer in women and the main cause of its mortality is induced by metastasizing to distant organs. Breast cancer primarily metastasizes to the bone, lung, liver and brain, and the bone is the most susceptible to metastasis. When breast cancer metastasizes to the bone, the dominant lesion is osteolytic. This osteolytic bone metastasis is highly associated with the complex interaction between cancer cells and the bone microenvironment. Interleukin-1 beta (IL-1β) and IL-17 act as osteolytic factors and promote osteolytic lesions in breast cancer pateints by increasing osteoclastogenesis and decreasing osteoblastogenesis. Especially, both of IL-1β and IL-17 increase in patients with breast cancer and decrease disease-free survival in cancer patients. Wogonin, one of the major flavonoids in the roots of Scutellaria baicalensis Georgi, has been recognized as a potent anti-cancer agent through increased apoptosis and decreased proliferation. We investigated whether wogonin could reduce the cancer cell-induced osteolysis by controlling interaction between cancer cells and bone-related cells. Wogonin suppressed cell viability, DNA synthesis and migration in MDA-MB 231 cells. Wogonin reduced the secretion of IL-1β and IL-17 in MDA-MB 231 cells. Wogonin at non-cytotoxic concentrations inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, wogonin blocked an increase in RANKL/osteoprotegerin mRNA ratio in the osteoblastic hFOB1.19 cells exposed to MDA-MB 231 cells-derived conditioned medium. Finally, oral administration of wogonin significantly inhibited osteolytic lesions in MDA-MB 231 cells-injected mice. Taken together, these results indicate that wogonin is a promising agent for preventing and treating cancer-cell mediated bone loss. Citation Format: Hyungkeun Kim, Kwang-Kyun Park, Won-Yoon Chung. Wogonin suppresses the production of breast cancer-derived osteolytic factors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1543. doi:10.1158/1538-7445.AM2015-1543

The Fine LINE: Methylation Drawing the Cancer Landscape.

LINE-1 (L1) is the most abundant mammalian transposable element that comprises nearly 20% of the genome, and nearly half of the mammalian genome has stemmed from L1-mediated mobilization. Expression and retrotransposition of L1 are suppressed by complex mechanisms, where the key role belongs to DNA methylation. Alterations in L1 methylation may lead to aberrant expression of L1 and have been described in numerous diseases. Accumulating evidence clearly indicates that loss of global DNA methylation observed in cancer development and progression is tightly associated with hypomethylation of L1 elements. Significant progress achieved in the last several years suggests that such parameters as L1 methylation status can be potentially utilized as clinical biomarkers for determination of the disease stage and in predicting the disease-free survival in cancer patients. In this paper, we summarize the current knowledge on L1 methylation, with specific emphasis given to success and challenges on the way of introduction of L1 into clinical practice.

Prognostic Value of Circulating Cytokines on Overall Survival and Disease-Free Survival in Cancer Patients

Through their tumor-promoting and/or tumor-suppressive properties, cytokines can influence progression of cancer. We systematically reviewed the current literature on the prognostic value of the circulating cytokines IL-1α/β, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-β and IFN-γ to predict overall and disease-free survival in any type of cancer patients. PubMed was systematically searched and based on eligibility assessment using our five criteria of the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) checklist, six unique studies were reviewed. Elevated IL-6 and IL-10 levels seem independently associated with worse prognosis in terms of overall and disease-free survival. The prognostic value of IL-1α/β, IL-8, IL-12, TNF-α, TGF-β and IFN-γ could not be demonstrated. The small number of selected studies underlines the need for large well-designed prospective studies, using the REMARK checklist as a guideline, to determine which cytokines have prognostic value on survival in cancer patients.

Immunotherapy Exposes Cancer Stem Cell Resistance and a New Synthetic Lethality

Development of resistance to targeted drugs and immunotherapy limits improvement in response rates and disease-free survival of cancer patients. In advanced melanoma, for example, multiple mechanisms of resistance emerge during BRAF inhibitor drug therapy that affect both tumor cell properties and microenvironment.1 In addition, just as immunoediting during the de novo immune response against cancer selects for immune-resistant tumor variants,2 active and passive immunotherapies can create selective pressures that lead to outgrowth of resistant tumor cells or new metastases (Figure 1). Understanding the mechanisms of resistance is critical to developing therapeutic strategies to counteract them as well as preventive measures to avoid their onset. In this issue of Molecular Therapy, Boisgerault and colleagues3 nicely elucidate these points using a tumor vaccination model to induce a T-cell response that places a selective pressure on the tumor facilitating the emergence or selective survival of resistant cancer stem cells or cells undergoing epithelial–mesenchymal transition (EMT). The study further shows how acquired or intrinsic mechanisms of resistance can reveal molecular vulnerabilities that may allow responses even to chemotherapy drugs that would have been considered ineffectual.

Abstract 3618: Peripheral cytokine profiles and prostate cancer risk in CLUE II.

Abstract Background Recent evidence suggests a role for inflammation in the etiology of prostate cancer. Cytokines are important regulators of immune response, including in cancer. In the context of cancer, Th1 cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and, to some extent, interleukin (IL)-6, can elicit immune reactions to tumor cells. IL-1β, IL-8, IL-10, and IL-12p70 may suppress immune response to a tumor. Immune profile may be an important prognostic factor for disease-free survival in cancer patients. Whether the circulating cytokine profile influences prostate cancer incidence is understudied. Thus, we evaluated the cytokine-prostate cancer association prospectively. Methods We conducted an age-race matched case-control study (268 pairs) of inflammatory cytokines (IFN-γ, IL-10, IL-12-p70, IL-1β, IL-6, IL-8, and TNF-α), measured using the ultrasensitive Meso Scale Discovery (MSD) platform, and incident prostate cancer in CLUE II. Cases were identified by cancer registry linkage. The odds ratio (OR) and 95% confidence interval (95% CI) of prostate cancer by quartile of cytokine was calculated using matched and multivariable-adjusted conditional logistic regression. Results Median concentrations of IFN-γ (p=0.002), TNF-α (p=0.04), and IL-6 (p=0.06) were lower in cases than controls. Concentrations of the other cytokines did not differ by case status. The multivariable-adjusted OR of prostate cancer decreased across quartiles of IFN-γ (p-trend=0.004), TNF-α (p-trend=0.03), and IL-6 (p-trend=0.005). After their mutual adjustment, the patterns of association remained the same. Of note, the highest (vs lowest) quartile of TNF-α (p=0.03) and IL-6 (p=0.001) was associated with lower risk of metastatic prostate cancer with high Gleason sum ≥7. Overall prostate cancer risk did not change across quartiles of the other cytokines, including IL-10, a Th2 cytokine. However, in normal weight men, higher IL-10 concentration was inversely associated with prostate cancer (highest vs lowest quartiles: OR=0.36; 95% CI: 0.19-0.68), whereas in overweight and obese men, IL-10 was not inversely associated with risk (OR=1.32; 95% CI: 0.87-1.97; p-interaction=0.001). Significant interactions with BMI were not observed for the other cytokines. Conclusion Men with a prediagnostic circulating cytokine profile indicative of Th1 immune response may have a lower risk of prostate cancer, including aggressive disease. Whether this circulating cytokine profile reflects 1) the intraprostatic immune environment in benign tissue that protects against the development of prostate cancer, 2) the immune milieu in response to a yet undetected prostate adenocarcinoma that inhibits its growth and thus detectability, and/or 3) a systemic immune profile that mediates the influence of modifiable factors on prostate cancer risk, warrants additional study. The IL-10-obesity interaction also warrants further study. Citation Format: Nrupen A. Bhavsar, Jay J. Bream, Alan K. Meeker, Charles G. Drake, Sarah B. Peskoe, Angelo M. De Marzo, William B. Isaacs, Elizabeth A. Platz. Peripheral cytokine profiles and prostate cancer risk in CLUE II. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3618. doi:10.1158/1538-7445.AM2013-3618

Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor

SRC-3/AIB1 (steroid receptor coactivator 3/amplified in breast cancer 1) is an authentic oncogene that contributes to the development of drug resistance and poor disease-free survival in cancer patients. Autophagy is also an important cell death mechanism that has tumor suppressor function. In this study, we identified macrophage migration inhibitory factor (MIF) as a novel target gene of SRC-3 and demonstrated its importance in cell survival. Specifically, we showed that MIF is a strong suppressor of autophagic cell death. We further showed that suppression of MIF, in turn, induced autophagic cell death, enhanced chemosensitivity and inhibited tumorigenesis in a xenograft mouse tumorigenesis model. Our study demonstrated that regulation of MIF expression and suppression of autophagic cell death is a potent mechanism by which SRC-3 contributes to increased chemoresistance and tumorigenicity.

Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma

Background:Suppressive immune cells present in tumour microenvironments are known to augment tumour growth and hamper efficacy of antitumour therapies. The amino-bisphosphonate Zoledronic acid (ZA) is considered as an antitumour agent, as recent studies showed that ZA prolongs disease-free survival in cancer patients. The exact mechanism is a topic of debate; it has been suggested that ZA targets tumour-associated macrophages (TAMs).Methods:We investigate the role of ZA on the myeloid differentiation to TAMs in murine mesothelioma in vivo and in vitro. Mice were intraperitoneally inoculated with a lethal dose of mesothelioma tumour cells and treated with ZA to determine the effects on myeloid differentiation and survival.Results:We show that ZA impaired myeloid differentiation. Inhibition of myeloid differentiation led to a reduction in TAMs, but the number of immature myeloid cells with myeloid-derived suppressor cell (MDSC) characteristics was increased. In addition, ZA affects the phenotype of macrophages leading to reduced level of TAM-associated cytokines in the tumour microenvironment. No improvement of survival was observed.Conclusion:We conclude that ZA leads to a reduction in macrophages and impairs polarisation towards an M2 phenotype, but this was associated with an increase in the number of immature myeloid cells, which might diminish the effects of ZA on survival.