Meredith S. Carson, Patrick D. Rädler, Jody E. Albright, Melissa A. VerHague, Erika T. Rezeli, Daniel Roth, John E. French, C. Perou, S. Hursting, M. Coleman
Obesity is an established risk and progression factor for triple-negative breast cancer (TNBC), but preclinical studies to delineate the mechanisms underlying the obesity-TNBC link as well as strategies to break that link are constrained by the lack of tumor models syngeneic to obesity-prone mouse strains. C3(1)/SV40 T-antigen (C3-TAg) transgenic mice on an FVB genetic background develop tumors with molecular and pathologic features that closely resemble human TNBC, but FVB mice are resistant to diet-induced obesity (DIO). Herein, we sought to develop transplantable C3-TAg cell lines syngeneic to C57BL/6 mice, an inbred mouse strain that is sensitive to DIO. We backcrossed FVB-Tg(C3-1-TAg)cJeg/JegJ to C57BL/6 mice for ten generations, and spontaneous tumors from those mice were excised and used to generate four clonal cell lines (B6TAg1.02, B6TAg2.03, B6TAg2.10, and B6TAg2.51). We characterized the growth of the four cell lines in both lean and DIO C57BL/6J female mice and performed transcriptomic profiling. Each cell line was readily tumorigenic and had transcriptional profiles that clustered as claudin-low, yet markedly differed from each other in their rate of tumor progression and transcriptomic signatures for key metabolic, immune, and oncogenic signaling pathways. DIO accelerated tumor growth of orthotopically transplanted B6TAg1.02, B6TAg2.03, and B6TAg2.51 cells. Thus, the B6TAg cell lines described herein offer promising and diverse new models to augment the study of DIO-associated TNBC.
肥胖是三阴性乳腺癌（TNBC）的一个既定风险和进展因素，但由于缺乏与易患肥胖症的小鼠品系共生的肿瘤模型，因此限制了旨在阐明肥胖与 TNBC 关联机制的临床前研究以及打破这种关联的策略。FVB遗传背景的C3(1)/SV40 T抗原（C3-TAg）转基因小鼠所患肿瘤的分子和病理特征与人类TNBC非常相似，但FVB小鼠对饮食诱导肥胖（DIO）有抵抗力。在此，我们试图开发可移植的 C3-TAg 细胞系，使其与对 DIO 敏感的近交系小鼠 C57BL/6 协同增殖。我们将FVB-Tg(C3-1-TAg)cJeg/JegJ与C57BL/6小鼠回交了十代，切除了这些小鼠的自发性肿瘤，并利用它们产生了四个克隆细胞系（B6TAg1.02、B6TAg2.03、B6TAg2.10和B6TAg2.51）。我们对这四种细胞系在瘦小鼠和 DIO C57BL/6J 雌性小鼠体内的生长情况进行了鉴定，并进行了转录组分析。每种细胞系都很容易致瘤，其转录特征都是低克劳丁，但它们的肿瘤进展速度和关键代谢、免疫和致癌信号通路的转录组特征却明显不同。DIO加速了正位移植的B6TAg1.02、B6TAg2.03和B6TAg2.51细胞的肿瘤生长。因此，本文描述的 B6TAg 细胞系为加强 DIO 相关 TNBC 的研究提供了前景广阔的多样化新模型。
{"title":"Development and Characterization of Syngeneic Orthotopic Transplant Models of Obesity-Responsive Triple-Negative Breast Cancer in C57BL/6J Mice","authors":"Meredith S. Carson, Patrick D. Rädler, Jody E. Albright, Melissa A. VerHague, Erika T. Rezeli, Daniel Roth, John E. French, C. Perou, S. Hursting, M. Coleman","doi":"10.3390/cancers16162803","DOIUrl":"https://doi.org/10.3390/cancers16162803","url":null,"abstract":"Obesity is an established risk and progression factor for triple-negative breast cancer (TNBC), but preclinical studies to delineate the mechanisms underlying the obesity-TNBC link as well as strategies to break that link are constrained by the lack of tumor models syngeneic to obesity-prone mouse strains. C3(1)/SV40 T-antigen (C3-TAg) transgenic mice on an FVB genetic background develop tumors with molecular and pathologic features that closely resemble human TNBC, but FVB mice are resistant to diet-induced obesity (DIO). Herein, we sought to develop transplantable C3-TAg cell lines syngeneic to C57BL/6 mice, an inbred mouse strain that is sensitive to DIO. We backcrossed FVB-Tg(C3-1-TAg)cJeg/JegJ to C57BL/6 mice for ten generations, and spontaneous tumors from those mice were excised and used to generate four clonal cell lines (B6TAg1.02, B6TAg2.03, B6TAg2.10, and B6TAg2.51). We characterized the growth of the four cell lines in both lean and DIO C57BL/6J female mice and performed transcriptomic profiling. Each cell line was readily tumorigenic and had transcriptional profiles that clustered as claudin-low, yet markedly differed from each other in their rate of tumor progression and transcriptomic signatures for key metabolic, immune, and oncogenic signaling pathways. DIO accelerated tumor growth of orthotopically transplanted B6TAg1.02, B6TAg2.03, and B6TAg2.51 cells. Thus, the B6TAg cell lines described herein offer promising and diverse new models to augment the study of DIO-associated TNBC.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"44 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huijie Liu, Ayse Ece Cali Daylan, Jihua Yang, Ankit Tanwar, Alain Borczuk, Dongwei Zhang, Vincent Chau, Shenduo Li, Xuan Ge, B. Halmos, Xingxing Zang, Haiying Cheng
Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA’s role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy.
尽管非小细胞肺癌（NSCLC）治疗取得了重大进展，但非癌基因驱动肿瘤患者的五年生存率仍然很低，因此有必要采取综合方法来改善预后。我们之前的高通量 RNAi 筛选发现极光激酶 A (AURKA) 是顺铂耐药的潜在关键参与者。在本研究中，我们研究了 AURKA 在多个 NSCLC 细胞系和异种移植小鼠模型中对铂和辐射敏感性的作用，以及它对免疫检查点（包括 PD-L1、B7x、B7-H3 和 HHLA2）的影响。在94例NSCLC患者肿瘤标本中，91.5%的标本检测出AURKA表达阳性，其中34%的标本显示中度至高度表达。NSCLC 细胞系 PC9 和 A549 经顺铂处理后，AURKA 表达上调。阿利舍替布抑制 AURKA 和诱导性 AURKA 敲除都能增强顺铂和辐射的细胞毒性作用，从而导致强力霉素诱导的异种移植小鼠肿瘤消退。联合处理的细胞表现出更多的 DNA 双链断裂、细胞凋亡和衰老。此外，阿利舍替布单独抑制 AURKA 会增加 PD-L1 和 B7-H3 的表达。总之，我们的研究表明，AURKA抑制能增强铂类化疗对NSCLC细胞的疗效，并调节多种免疫检查点的表达。因此，在化疗免疫疗法不断发展的背景下，应战略性地设计并进一步研究与AURKA抑制剂的联合治疗方案。
{"title":"Aurora Kinase A Inhibition Potentiates Platinum and Radiation Cytotoxicity in Non-Small-Cell Lung Cancer Cells and Induces Expression of Alternative Immune Checkpoints","authors":"Huijie Liu, Ayse Ece Cali Daylan, Jihua Yang, Ankit Tanwar, Alain Borczuk, Dongwei Zhang, Vincent Chau, Shenduo Li, Xuan Ge, B. Halmos, Xingxing Zang, Haiying Cheng","doi":"10.3390/cancers16162805","DOIUrl":"https://doi.org/10.3390/cancers16162805","url":null,"abstract":"Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA’s role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"10 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141921229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Daily clinical practice requires repeated and prolonged venous access for delivering chemotherapy, antibiotics, antivirals, parenteral nutrition, or blood transfusions. This study aimed to investigate the performance and the safety of totally implantable vascular access devices (TIVADs) over a 5-year follow-up period through a standardized well-trained surgical technique and patient management under local anesthesia. Methods: In a retrospective, observational, and monocentric study, 70 patients receiving POLYSITE® TIVADs for chemotherapy were included. The safety endpoints focused on the rate of perioperative, short-term, and long-term complications. The performance endpoints included vein identification for device insertion and procedural success rate. Results: The study demonstrated no perioperative or short-term complications related to the TIVADs. One (1.4%) complication related to device manipulation was identified as catheter flipping, which led to catheter adjustment 56 days post-placement. Moreover, one (1.4%) infection due to usage conditions was observed, leading to TIVAD removal 3 years and 4 months post-surgery. Catheter placement occurred in cephalic veins (71.4%), subclavian veins (20%), and internal jugular veins (8.6%). The procedural success rate was 100%. Overall, the implantable ports typically remained in place for an average of 22.4 months. Conclusions: This study confirmed the TIVADs’ performance and safety, underscored by low complication rates compared to published data, thereby emphasizing its potential and compelling significance for enhancing routine clinical practice using a standardized well-trained surgical technique and patient management.
{"title":"A Monocentric Analysis of Implantable Ports in Cancer Treatment: Five-Year Efficacy and Safety Evaluation","authors":"Adel Abou-Mrad, Luigi Marano, Rodolfo J Oviedo","doi":"10.3390/cancers16162802","DOIUrl":"https://doi.org/10.3390/cancers16162802","url":null,"abstract":"Background: Daily clinical practice requires repeated and prolonged venous access for delivering chemotherapy, antibiotics, antivirals, parenteral nutrition, or blood transfusions. This study aimed to investigate the performance and the safety of totally implantable vascular access devices (TIVADs) over a 5-year follow-up period through a standardized well-trained surgical technique and patient management under local anesthesia. Methods: In a retrospective, observational, and monocentric study, 70 patients receiving POLYSITE® TIVADs for chemotherapy were included. The safety endpoints focused on the rate of perioperative, short-term, and long-term complications. The performance endpoints included vein identification for device insertion and procedural success rate. Results: The study demonstrated no perioperative or short-term complications related to the TIVADs. One (1.4%) complication related to device manipulation was identified as catheter flipping, which led to catheter adjustment 56 days post-placement. Moreover, one (1.4%) infection due to usage conditions was observed, leading to TIVAD removal 3 years and 4 months post-surgery. Catheter placement occurred in cephalic veins (71.4%), subclavian veins (20%), and internal jugular veins (8.6%). The procedural success rate was 100%. Overall, the implantable ports typically remained in place for an average of 22.4 months. Conclusions: This study confirmed the TIVADs’ performance and safety, underscored by low complication rates compared to published data, thereby emphasizing its potential and compelling significance for enhancing routine clinical practice using a standardized well-trained surgical technique and patient management.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"12 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141925170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jesus Romero Fernandez, Sofia Cordoba Largo, R. Benlloch Rodriguez, Beatriz Gil Haro
Radiobiology has evolved from a mechanistic model based on DNA damage and response factors into a more complex model that includes effects on the immune system and the tumor microenvironment (TME). Irradiation has an immunomodulatory effect that can manifest as increased anti-tumor immunity or immunosuppression. Irradiation promotes an inflammatory microenvironment through the release of pro-inflammatory cytokines and endothelial damage, which recruit immune system cells to the irradiated area. Radiation-induced immunogenic cell death (ICD), characterized by the release of damage-associated molecular patterns (DAMPs) and tumor antigens, triggers an anti-tumor immune response of both innate and adaptive immunity. Anti-tumor immunity can manifest at a distance from the irradiated area, a phenomenon known as the abscopal effect (AE), which involves dendritic cells and CD8+ T cells. Irradiation also produces an immunosuppressive effect mediated by tumor-associated macrophages (TAMs) and regulatory T lymphocytes (Tregs), which counterbalances the immunostimulatory effect. In this work, we review the mechanisms involved in the radiation-induced immune response, which support the combined treatment of RT and immunotherapy, focusing, where possible, on gynecologic cancer.
放射生物学已从基于 DNA 损伤和反应因子的机理模型发展为一个更复杂的模型，其中包括对免疫系统和肿瘤微环境（TME）的影响。辐照具有免疫调节作用，可表现为抗肿瘤免疫力增强或免疫抑制。辐照通过释放促炎细胞因子和内皮损伤促进炎性微环境，从而将免疫系统细胞招引到辐照区域。辐射诱导的免疫性细胞死亡（ICD）的特点是释放损伤相关分子模式（DAMPs）和肿瘤抗原，从而引发先天性免疫和适应性免疫的抗肿瘤免疫反应。抗肿瘤免疫可在远离辐照区域的地方表现出来，这种现象被称为缺席效应（AE），涉及树突状细胞和 CD8+ T 细胞。辐照还会产生由肿瘤相关巨噬细胞（TAMs）和调节性 T 淋巴细胞（Tregs）介导的免疫抑制效应，从而抵消免疫刺激效应。在这项工作中，我们回顾了辐射诱导免疫反应的相关机制，这些机制支持 RT 和免疫疗法的联合治疗，并尽可能以妇科癌症为重点。
{"title":"The Effects of Gynecological Tumor Irradiation on the Immune System","authors":"Jesus Romero Fernandez, Sofia Cordoba Largo, R. Benlloch Rodriguez, Beatriz Gil Haro","doi":"10.3390/cancers16162804","DOIUrl":"https://doi.org/10.3390/cancers16162804","url":null,"abstract":"Radiobiology has evolved from a mechanistic model based on DNA damage and response factors into a more complex model that includes effects on the immune system and the tumor microenvironment (TME). Irradiation has an immunomodulatory effect that can manifest as increased anti-tumor immunity or immunosuppression. Irradiation promotes an inflammatory microenvironment through the release of pro-inflammatory cytokines and endothelial damage, which recruit immune system cells to the irradiated area. Radiation-induced immunogenic cell death (ICD), characterized by the release of damage-associated molecular patterns (DAMPs) and tumor antigens, triggers an anti-tumor immune response of both innate and adaptive immunity. Anti-tumor immunity can manifest at a distance from the irradiated area, a phenomenon known as the abscopal effect (AE), which involves dendritic cells and CD8+ T cells. Irradiation also produces an immunosuppressive effect mediated by tumor-associated macrophages (TAMs) and regulatory T lymphocytes (Tregs), which counterbalances the immunostimulatory effect. In this work, we review the mechanisms involved in the radiation-induced immune response, which support the combined treatment of RT and immunotherapy, focusing, where possible, on gynecologic cancer.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"27 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giovanni Taffurelli, I. Montroni, Claudia Dileo, A. Boccaccino, F. Ghignone, D. Zattoni, Giacomo Frascaroli, Giampaolo Ugolini
Background: Managing patients with obstructing rectal cancer is challenging due to the risks of gastrointestinal obstruction and perforation. This study evaluates the outcomes of pre-emptive laparoscopic colostomy creation in patients with locally advanced rectal and anal cancer to prevent symptoms and facilitate therapy initiation. Methods: This retrospective cohort study includes patients with locally advanced rectal or anal cancer assessed by our Colorectal Multidisciplinary Team from January 2017 to February 2024. Patients who underwent pre-emptive laparoscopic colostomy were compared to a control group of non-obstructing rectal cancer patients who started direct oncological treatment. The primary endpoint was the time from diagnosis to the initiation of oncological treatments. The secondary endpoints were the rate and timing of subsequent radical resection, surgical morbidity and hospital stay. A Weibull regression was used to evaluate the time differences between the groups. Results: There were 37 patients who received pre-emptive laparoscopic colostomy, compared to 207 control patients. The mean time from diagnosis to the start of neoadjuvant therapy was 38.3 ± 2.3 days. Despite higher rates of malnutrition and more advanced stages in the colostomy group, no significant differences were observed in the time to start therapy (p = 0.083) or time to radical resection (p = 0.187) between the groups. The laparoscopic procedure showed low rates of postoperative complications and acceptable lengths of stay. Discussion and Conclusions: Pre-emptive laparoscopic colostomy is a feasible approach for managing obstructing rectal or anal cancer. Treatment timelines were not extended compared to timelines for non-obstructing cases, despite differences in nutritional status and staging. Further prospective studies with larger cohorts are needed to validate these findings and refine treatment protocols for obstructing gastrointestinal malignancies.
{"title":"Pre-emptive Laparoscopic Colostomy Creation in Obstructing Locally Advanced Rectal and Anal Cancer Does Not Delay the Starting of Oncological Treatments","authors":"Giovanni Taffurelli, I. Montroni, Claudia Dileo, A. Boccaccino, F. Ghignone, D. Zattoni, Giacomo Frascaroli, Giampaolo Ugolini","doi":"10.3390/cancers16162799","DOIUrl":"https://doi.org/10.3390/cancers16162799","url":null,"abstract":"Background: Managing patients with obstructing rectal cancer is challenging due to the risks of gastrointestinal obstruction and perforation. This study evaluates the outcomes of pre-emptive laparoscopic colostomy creation in patients with locally advanced rectal and anal cancer to prevent symptoms and facilitate therapy initiation. Methods: This retrospective cohort study includes patients with locally advanced rectal or anal cancer assessed by our Colorectal Multidisciplinary Team from January 2017 to February 2024. Patients who underwent pre-emptive laparoscopic colostomy were compared to a control group of non-obstructing rectal cancer patients who started direct oncological treatment. The primary endpoint was the time from diagnosis to the initiation of oncological treatments. The secondary endpoints were the rate and timing of subsequent radical resection, surgical morbidity and hospital stay. A Weibull regression was used to evaluate the time differences between the groups. Results: There were 37 patients who received pre-emptive laparoscopic colostomy, compared to 207 control patients. The mean time from diagnosis to the start of neoadjuvant therapy was 38.3 ± 2.3 days. Despite higher rates of malnutrition and more advanced stages in the colostomy group, no significant differences were observed in the time to start therapy (p = 0.083) or time to radical resection (p = 0.187) between the groups. The laparoscopic procedure showed low rates of postoperative complications and acceptable lengths of stay. Discussion and Conclusions: Pre-emptive laparoscopic colostomy is a feasible approach for managing obstructing rectal or anal cancer. Treatment timelines were not extended compared to timelines for non-obstructing cases, despite differences in nutritional status and staging. Further prospective studies with larger cohorts are needed to validate these findings and refine treatment protocols for obstructing gastrointestinal malignancies.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mark Marsland, Chen Chen Jiang, Sam Faulkner, A. Steigler, Kristen McEwan, Phillip Jobling, Christopher Oldmeadow, Brett Delahunt, James W. Denham, Hubert Hondermarck
This study investigated the prognostic value of the chemokine C-C motif ligand 2 (CCL2) and its receptor C-C motif chemokine receptor 2 (CCR2) expression in locally advanced prostate cancer treated with radiotherapy and androgen deprivation using the 10-year outcome data from the TROG 03.04 RADAR clinical trial. CCL2 and CCR2 protein expression in prostate cancer biopsies at the time of diagnosis were quantified by immunohistochemistry and digital quantification. CCR2 protein expression was detected in prostate cancer cells and was associated with prostate-specific antigen serum concentration (p = 0.045). However, neither CCL2 nor CCR2 tissue expression could predict prostate cancer progression, or other clinicopathological parameters including perineural invasion and patient outcome. In serum samples, CCL2 concentration at the time of diagnosis, as assayed by enzyme-linked immunosorbent assay, was significantly higher in patients with prostate cancer compared with benign prostatic hyperplasia (median difference 0.22 ng/mL, 95% CI, 0.17–0.30) (p < 0.0001) and normal controls (median difference 0.13 ng/mL, 95% CI, 0.13–0.17) (p < 0.0001). However, circulating CCL2 was not statistically significant as a predictor of disease progression and patient outcome. In conclusion, this study shows that although CCL2 and CCR2 are expressed in prostate cancer, with an increased level of CCL2 in the serum, neither CCL2 nor CCR2 expression has a clinical prognostic value in locally advanced prostate cancer.
{"title":"CCL2/CCR2 Expression in Locally Advanced Prostate Cancer and Patient Long-Term Outcome: 10-Year Results from the TROG 03.04 RADAR Trial","authors":"Mark Marsland, Chen Chen Jiang, Sam Faulkner, A. Steigler, Kristen McEwan, Phillip Jobling, Christopher Oldmeadow, Brett Delahunt, James W. Denham, Hubert Hondermarck","doi":"10.3390/cancers16162794","DOIUrl":"https://doi.org/10.3390/cancers16162794","url":null,"abstract":"This study investigated the prognostic value of the chemokine C-C motif ligand 2 (CCL2) and its receptor C-C motif chemokine receptor 2 (CCR2) expression in locally advanced prostate cancer treated with radiotherapy and androgen deprivation using the 10-year outcome data from the TROG 03.04 RADAR clinical trial. CCL2 and CCR2 protein expression in prostate cancer biopsies at the time of diagnosis were quantified by immunohistochemistry and digital quantification. CCR2 protein expression was detected in prostate cancer cells and was associated with prostate-specific antigen serum concentration (p = 0.045). However, neither CCL2 nor CCR2 tissue expression could predict prostate cancer progression, or other clinicopathological parameters including perineural invasion and patient outcome. In serum samples, CCL2 concentration at the time of diagnosis, as assayed by enzyme-linked immunosorbent assay, was significantly higher in patients with prostate cancer compared with benign prostatic hyperplasia (median difference 0.22 ng/mL, 95% CI, 0.17–0.30) (p < 0.0001) and normal controls (median difference 0.13 ng/mL, 95% CI, 0.13–0.17) (p < 0.0001). However, circulating CCL2 was not statistically significant as a predictor of disease progression and patient outcome. In conclusion, this study shows that although CCL2 and CCR2 are expressed in prostate cancer, with an increased level of CCL2 in the serum, neither CCL2 nor CCR2 expression has a clinical prognostic value in locally advanced prostate cancer.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"22 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141925696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shauna McClelland, P. Maxwell, Cristina Branco, Simon T Barry, C. Eberlein, Melissa J. LaBonte
This review delves into the intricate roles of interleukin-8 (IL-8) and its receptors, CXCR1 and CXCR2, in prostate cancer (PCa), particularly in castration-resistant (CRPC) and metastatic CRPC (mCRPC). This review emphasizes the crucial role of the tumour microenvironment (TME) and inflammatory cytokines in promoting tumour progression and response to tumour cell targeting agents. IL-8, acting through C-X-C chemokine receptor type 1 (CXCR1) and type 2 (CXCR2), modulates multiple signalling pathways, enhancing the angiogenesis, proliferation, and migration of cancer cells. This review highlights the shift in PCa research focus from solely tumour cells to the non-cancer-cell components, including vascular endothelial cells, the extracellular matrix, immune cells, and the dynamic interactions within the TME. The immunosuppressive nature of the PCa TME significantly influences tumour progression and resistance to emerging therapies. Current treatment modalities, including androgen deprivation therapy and chemotherapeutics, encounter persistent resistance and are complicated by prostate cancer’s notably “immune-cold” nature, which limits immune system response to the tumour. These challenges underscore the critical need for novel approaches that both overcome resistance and enhance immune engagement within the TME. The therapeutic potential of inhibiting IL-8 signalling is explored, with studies showing enhanced sensitivity of PCa cells to treatments, including radiation and androgen receptor inhibitors. Clinical trials, such as the ACE trial, demonstrate the efficacy of combining CXCR2 inhibitors with existing treatments, offering significant benefits, especially for patients with resistant PCa. This review also addresses the challenges in targeting cytokines and chemokines, noting the complexity of the TME and the need for precision in therapeutic targeting to avoid side effects and optimize outcomes.
{"title":"Targeting IL-8 and Its Receptors in Prostate Cancer: Inflammation, Stress Response, and Treatment Resistance","authors":"Shauna McClelland, P. Maxwell, Cristina Branco, Simon T Barry, C. Eberlein, Melissa J. LaBonte","doi":"10.3390/cancers16162797","DOIUrl":"https://doi.org/10.3390/cancers16162797","url":null,"abstract":"This review delves into the intricate roles of interleukin-8 (IL-8) and its receptors, CXCR1 and CXCR2, in prostate cancer (PCa), particularly in castration-resistant (CRPC) and metastatic CRPC (mCRPC). This review emphasizes the crucial role of the tumour microenvironment (TME) and inflammatory cytokines in promoting tumour progression and response to tumour cell targeting agents. IL-8, acting through C-X-C chemokine receptor type 1 (CXCR1) and type 2 (CXCR2), modulates multiple signalling pathways, enhancing the angiogenesis, proliferation, and migration of cancer cells. This review highlights the shift in PCa research focus from solely tumour cells to the non-cancer-cell components, including vascular endothelial cells, the extracellular matrix, immune cells, and the dynamic interactions within the TME. The immunosuppressive nature of the PCa TME significantly influences tumour progression and resistance to emerging therapies. Current treatment modalities, including androgen deprivation therapy and chemotherapeutics, encounter persistent resistance and are complicated by prostate cancer’s notably “immune-cold” nature, which limits immune system response to the tumour. These challenges underscore the critical need for novel approaches that both overcome resistance and enhance immune engagement within the TME. The therapeutic potential of inhibiting IL-8 signalling is explored, with studies showing enhanced sensitivity of PCa cells to treatments, including radiation and androgen receptor inhibitors. Clinical trials, such as the ACE trial, demonstrate the efficacy of combining CXCR2 inhibitors with existing treatments, offering significant benefits, especially for patients with resistant PCa. This review also addresses the challenges in targeting cytokines and chemokines, noting the complexity of the TME and the need for precision in therapeutic targeting to avoid side effects and optimize outcomes.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"14 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rebecca Houston, Shivum Desai, Ariel Takayanagi, Christina Quynh Thu Tran, Ali Mortezaei, Alireza Oladaskari, Arman Sourani, Imran Siddiqi, Behnood Khodayari, Allen Ho, Omid Hariri
Spinal metastases occur in up to 40% of patients with cancer. Of these cases, 10% become symptomatic. The reported incidence of spinal metastases has increased in recent years due to innovations in imaging modalities and oncological treatments. As the incidence of spinal metastases rises, so does the demand for improved treatments and treatment algorithms, which now emphasize greater multidisciplinary collaboration and are increasingly customized per patient. Uniquely, we discuss the potential clinical applications of AI and NGS in the treatment of spinal metastases. Material and Methods: A PubMed search for articles published from 2000 to 2023 regarding spinal metastases and artificial intelligence in healthcare was completed. After screening for relevance, the key findings from each study were summarized in this update. Results: This review summarizes the evidence from studies reporting on treatment modalities for spinal metastases, including minimally invasive surgery (MIS), external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), CFR-PEEK instrumentation, radiofrequency ablation (RFA), next-generation sequencing (NGS), artificial intelligence, and predictive models.
{"title":"A Multidisciplinary Update on Treatment Modalities for Metastatic Spinal Tumors with a Surgical Emphasis: A Literature Review and Evaluation of the Role of Artificial Intelligence","authors":"Rebecca Houston, Shivum Desai, Ariel Takayanagi, Christina Quynh Thu Tran, Ali Mortezaei, Alireza Oladaskari, Arman Sourani, Imran Siddiqi, Behnood Khodayari, Allen Ho, Omid Hariri","doi":"10.3390/cancers16162800","DOIUrl":"https://doi.org/10.3390/cancers16162800","url":null,"abstract":"Spinal metastases occur in up to 40% of patients with cancer. Of these cases, 10% become symptomatic. The reported incidence of spinal metastases has increased in recent years due to innovations in imaging modalities and oncological treatments. As the incidence of spinal metastases rises, so does the demand for improved treatments and treatment algorithms, which now emphasize greater multidisciplinary collaboration and are increasingly customized per patient. Uniquely, we discuss the potential clinical applications of AI and NGS in the treatment of spinal metastases. Material and Methods: A PubMed search for articles published from 2000 to 2023 regarding spinal metastases and artificial intelligence in healthcare was completed. After screening for relevance, the key findings from each study were summarized in this update. Results: This review summarizes the evidence from studies reporting on treatment modalities for spinal metastases, including minimally invasive surgery (MIS), external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), CFR-PEEK instrumentation, radiofrequency ablation (RFA), next-generation sequencing (NGS), artificial intelligence, and predictive models.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"14 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Sesma, Juli á n Pardo, Dolores Isla, Eva M. Gálvez, M. Gascón-Ruiz, Luis Martínez-Lostao, Alba Moratiel, J. R. Paño-Pardo, E. Quílez, I. Torres-Ramón, A. Yubero, M. Zapata-García, Mar í a Pilar Domingo, Patricia Esteban, Rebeca Sanz Pamplona, Rodrigo Lastra, A. Ramírez-Labrada
The development of immune checkpoint inhibitors (ICIs) has changed the therapeutic paradigm of lung cancer (LC), becoming the standard of treatment for previously untreated advanced non-small cell lung cancer (NSCLC) without actionable mutations. It has allowed the achievement of durable responses and resulted in significant survival benefits. However, not all patients respond; hence, molecular biomarkers are needed to help us predict which patients will respond. With this objective, a prospective observational study was designed, including a cohort of 55 patients with NSCLC who received ICIs. We studied whether biomarkers such as TCRβ and specific cytokines involved in the regulation of T cell activity were related to the immunotherapy response. In the survival analysis, it was found that patients with higher TCRβ clonality, lower TCRβ evenness, higher TCRβ Shannon diversity and lower TCRβ convergence had higher overall survival (OS) and progression-free survival (PFS). However, no statistically significant association was observed. Regarding cytokines, those patients with higher levels of IL-2 and IL-15 presented statistically significantly shorter OS and PFS, respectively. In fact, in the multivariable analysis, the high IL-15 level increased the risk of death by three times. Although the sample size was small and more studies are needed to confirm our results, our study reveals promising markers of responses to ICIs.
免疫检查点抑制剂（ICIs）的开发改变了肺癌（LC）的治疗模式，成为治疗先前未经治疗且无可作用突变的晚期非小细胞肺癌（NSCLC）的标准疗法。该疗法可获得持久的疗效，并为患者带来显著的生存益处。然而，并非所有患者都会产生反应；因此，我们需要分子生物标志物来帮助我们预测哪些患者会产生反应。为此，我们设计了一项前瞻性观察研究，研究对象包括55名接受过ICIs治疗的NSCLC患者。我们研究了TCRβ和参与调节T细胞活性的特定细胞因子等生物标志物是否与免疫疗法反应有关。在生存期分析中，我们发现TCRβ克隆度较高、TCRβ均匀度较低、TCRβ香农多样性较高和TCRβ收敛性较低的患者总生存期（OS）和无进展生存期（PFS）较高。然而，在统计学上没有观察到明显的关联。在细胞因子方面，IL-2 和 IL-15 水平较高的患者的 OS 和 PFS 分别明显较短。事实上，在多变量分析中，IL-15水平高的患者死亡风险增加了三倍。虽然样本量较小，需要更多的研究来证实我们的结果，但我们的研究揭示了对 ICIs 反应的有希望的标志物。
{"title":"Peripheral Blood TCRβ Repertoire, IL15, IL2 and Soluble Ligands for NKG2D Activating Receptor Predict Efficacy of Immune Checkpoint Inhibitors in Lung Cancer","authors":"A. Sesma, Juli á n Pardo, Dolores Isla, Eva M. Gálvez, M. Gascón-Ruiz, Luis Martínez-Lostao, Alba Moratiel, J. R. Paño-Pardo, E. Quílez, I. Torres-Ramón, A. Yubero, M. Zapata-García, Mar í a Pilar Domingo, Patricia Esteban, Rebeca Sanz Pamplona, Rodrigo Lastra, A. Ramírez-Labrada","doi":"10.3390/cancers16162798","DOIUrl":"https://doi.org/10.3390/cancers16162798","url":null,"abstract":"The development of immune checkpoint inhibitors (ICIs) has changed the therapeutic paradigm of lung cancer (LC), becoming the standard of treatment for previously untreated advanced non-small cell lung cancer (NSCLC) without actionable mutations. It has allowed the achievement of durable responses and resulted in significant survival benefits. However, not all patients respond; hence, molecular biomarkers are needed to help us predict which patients will respond. With this objective, a prospective observational study was designed, including a cohort of 55 patients with NSCLC who received ICIs. We studied whether biomarkers such as TCRβ and specific cytokines involved in the regulation of T cell activity were related to the immunotherapy response. In the survival analysis, it was found that patients with higher TCRβ clonality, lower TCRβ evenness, higher TCRβ Shannon diversity and lower TCRβ convergence had higher overall survival (OS) and progression-free survival (PFS). However, no statistically significant association was observed. Regarding cytokines, those patients with higher levels of IL-2 and IL-15 presented statistically significantly shorter OS and PFS, respectively. In fact, in the multivariable analysis, the high IL-15 level increased the risk of death by three times. Although the sample size was small and more studies are needed to confirm our results, our study reveals promising markers of responses to ICIs.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeffrey C. Thompson, Caitlin M Tilsed, Christiana W. Davis, Aasha Gupta, Bihui Melidosian, Chifei Sun, Michael E Kallen, Cynthia Timmers, Corey J. Langer, Steven M. Albelda
Although immune checkpoint blockade (ICB) is currently approved for the treatment of extensive-stage small-cell lung cancer (SCLC) in combination with chemotherapy, relatively few patients have demonstrated durable clinical benefit (DCB) to these therapies. Biomarkers predicting responses are needed. Biopsies from 35 SCLC patients treated with ICB were subjected to transcriptomic analysis; gene signatures were assessed for associations with responses. Twenty-one patients were treated with ICB in the first-line setting in combination with platinum-based chemotherapy; fourteen patients were treated in the second-line setting with ICB alone. DCB after ICB in SCLC in the second-line setting (3 of 14 patients) was associated with statistically higher transcriptomic levels of genes associated with inflammation (p = 0.003), antigen presentation machinery (p = 0.03), interferon responses (p < 0.05), and increased CD8 T cells (p = 0.02). In contrast, these gene signatures were not significantly different in the first-line setting. Our data suggest that responses to ICB in SCLC in the second-line setting can be predicted by the baseline inflammatory state of the tumor; however, this strong association with inflammation was not seen in the first-line setting. We postulate that chemotherapy alters the immune milieu allowing a response to ICB. Other biomarkers will be needed to predict responses in first-line therapy patients.
{"title":"Predictive Signatures for Responses to Checkpoint Blockade in Small-Cell Lung Cancer in Second-Line Therapy Do Not Predict Responses in First-Line Patients","authors":"Jeffrey C. Thompson, Caitlin M Tilsed, Christiana W. Davis, Aasha Gupta, Bihui Melidosian, Chifei Sun, Michael E Kallen, Cynthia Timmers, Corey J. Langer, Steven M. Albelda","doi":"10.3390/cancers16162795","DOIUrl":"https://doi.org/10.3390/cancers16162795","url":null,"abstract":"Although immune checkpoint blockade (ICB) is currently approved for the treatment of extensive-stage small-cell lung cancer (SCLC) in combination with chemotherapy, relatively few patients have demonstrated durable clinical benefit (DCB) to these therapies. Biomarkers predicting responses are needed. Biopsies from 35 SCLC patients treated with ICB were subjected to transcriptomic analysis; gene signatures were assessed for associations with responses. Twenty-one patients were treated with ICB in the first-line setting in combination with platinum-based chemotherapy; fourteen patients were treated in the second-line setting with ICB alone. DCB after ICB in SCLC in the second-line setting (3 of 14 patients) was associated with statistically higher transcriptomic levels of genes associated with inflammation (p = 0.003), antigen presentation machinery (p = 0.03), interferon responses (p < 0.05), and increased CD8 T cells (p = 0.02). In contrast, these gene signatures were not significantly different in the first-line setting. Our data suggest that responses to ICB in SCLC in the second-line setting can be predicted by the baseline inflammatory state of the tumor; however, this strong association with inflammation was not seen in the first-line setting. We postulate that chemotherapy alters the immune milieu allowing a response to ICB. Other biomarkers will be needed to predict responses in first-line therapy patients.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":"57 44","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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