MDPI - Publisher of Open Access Journals

16 pages, 3527 KiB

Open AccessArticle

Treatment-Induced Gene Expression Changes in Metastatic Renal Cell Carcinoma: Insights from a Syngeneic Mouse Model

by Ko Okabe, Toshiaki Tanaka, Tetsuya Shindo, Yuki Kyoda, Sachiyo Nishida, Kohei Hashimoto, Ko Kobayashi and Naoya Masumori

Curr. Oncol. 2025, 32(7), 391; https://doi.org/10.3390/curroncol32070391 - 8 Jul 2025

Viewed by 463

Abstract

This study aimed to clarify the alterations in gene expression in metastatic renal cell carcinoma (mRCC) during disease progression and in response to treatment with immune checkpoint inhibitors using a syngeneic mouse mRCC model. RENCA cells were orthotopically implanted in BALB/c mice. Mice received first-line treatment with cabozantinib, anti-PD-1 antibody, or a combination. Tumor progression was monitored using serial micro-computed tomography. Lung metastasis samples were collected, and RNA sequencing was performed. Mice with apparent disease progression received second-line treatment with axitinib, everolimus, or lenvatinib after combination therapy. The median overall survival was 28, 34, 34, and 49 days in untreated mice and those treated with cabozantinib, anti-PD-1, or their combination, respectively (p < 0.05). RNA sequencing revealed upregulation of the fibroblast growth factor pathway in lung metastases after monotherapy, whereas mTOR pathway activation was observed only after combination therapy. Treatment-specific gene expression changes occur in mRCC, suggesting that the optimal target for sequential therapy in mRCC varies depending on prior treatment. Full article

(This article belongs to the Special Issue Resistance to Chemotherapy and Targeted Therapy in Cancer: Understanding the Pathogenesis and Identifying the Best Approaches to Overcome This Challenge)

► Show Figures

Figure 1

13 pages, 1420 KiB

Open AccessArticle

Knockdown of Antisense Noncoding Mitochondrial RNA Reduces Tumorigenicity of Patient-Derived Clear Cell Renal Carcinoma Cells in an Orthotopic Xenograft Mouse Model

by Mariela Araya, Francisca Sepúlveda, Jaime Villegas, Luis Alarcón, Luis O. Burzio, Verónica A. Burzio and Vincenzo Borgna

Cancers 2024, 16(4), 830; https://doi.org/10.3390/cancers16040830 - 19 Feb 2024

Cited by 2 | Viewed by 2244

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer and its treatment is hindered by a resistance to targeted therapies, immunotherapies and combinations of both. We have reported that the knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) with chemically modified antisense oligonucleotides induces proliferative arrest and apoptotic death in tumor cells from many human and mouse cancer types. These studies have been mostly performed in vitro and in vivo on commercially available cancer cell lines and have shown that in mouse models tumor growth is stunted by the treatment. The present work was performed on cells derived from primary and metastatic ccRCC tumors. We established primary cultures from primary and metastatic ccRCC tumors, which were subjected to knockdown of ASncmtRNAs in vitro and in vivo in an orthotopic xenograft model in NOD/SCID mice. We found that these primary ccRCC cells are affected in the same way as tumor cell lines and in the orthotopic model tumor growth was significantly reduced by the treatment. This study on patient-derived ccRCC tumor cells represents a model closer to actual patient ccRCC tumors and shows that knockdown of ASncmtRNAs poses a potential treatment option for these patients. Full article

(This article belongs to the Special Issue Mitochondria as Targets for Cancer Therapy)

► Show Figures

Figure 1

14 pages, 2912 KiB

Open AccessArticle

Near-Infrared Imaging of Colonic Adenomas In Vivo Using Orthotopic Human Organoids for Early Cancer Detection

by Xiaoli Wu, Chun-Wei Chen, Sangeeta Jaiswal, Tse-Shao Chang, Ruoliu Zhang, Michael K. Dame, Yuting Duan, Hui Jiang, Jason R. Spence, Sen-Yung Hsieh and Thomas D. Wang

Cancers 2023, 15(19), 4795; https://doi.org/10.3390/cancers15194795 - 29 Sep 2023

Cited by 2 | Viewed by 1791

Abstract

Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide. Premalignant lesions that are flat and subtle in morphology are often missed in conventional colonoscopies. Patient-derived adenoma colonoids with high and low cMet expression and normal colonoids were implanted orthotopically in the colon of immunocompromised mice to serve as a preclinical model system. A peptide specific for cMet was labeled with IRDye800, a near-infrared (NIR) fluorophore. This peptide was administered intravenously, and in vivo imaging was performed using a small animal fluorescence endoscope. Quantified intensities showed a peak target-to-background ratio at ~1 h after intravenous peptide injection, and the signal cleared by ~24 h. The peptide was stable in serum with a half-life of 3.6 h. Co-staining of adenoma and normal colonoids showed a high correlation between peptide and anti-cMet antibody. A human-specific cytokeratin stain verified the presence of human tissues implanted among surrounding normal mouse colonic mucosa. Peptide biodistribution was consistent with rapid renal clearance. No signs of acute toxicity were found on either animal necropsy or serum hematology and chemistries. Human colonoids provide a clinically relevant preclinical model to evaluate the specific uptake of a NIR peptide to detect premalignant colonic lesions in vivo. Full article

(This article belongs to the Section Cancer Biomarkers)

► Show Figures

Graphical abstract

20 pages, 4127 KiB

Open AccessArticle

Discovery of VIP236, an αvβ3-Targeted Small-Molecule–Drug Conjugate with Neutrophil Elastase-Mediated Activation of 7-Ethyl Camptothecin Payload for Treatment of Solid Tumors

by Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Melanie Heroult, Dmitry Zubov, Kersten Matthias Gericke, Harvey Wong, Melanie M. Frigault, Amy J. Johnson, Raquel Izumi and Ahmed Hamdy

Cancers 2023, 15(17), 4381; https://doi.org/10.3390/cancers15174381 - 1 Sep 2023

Cited by 6 | Viewed by 3986

Abstract

The emerging field of small-molecule–drug conjugates (SMDCs) using small-molecule biomarker-targeted compounds for tumor homing may provide new perspectives for targeted delivery. Here, for the first time, we disclose the structure and the synthesis of VIP236, an SMDC designed for the treatment of metastatic solid tumors by targeting αvβ3 integrins and extracellular cleavage of the 7-ethyl camptothecin payload by neutrophil elastase in the tumor microenvironment. Imaging studies in the Lewis lung mouse model using an elastase cleavable quenched substrate showed pronounced elastase activity in the tumor. Pharmacokinetics studies of VIP236 in tumor-bearing mice demonstrated high stability of the SMDC in plasma and high tumor accumulation of the cleaved payload. Studies in bile-duct-cannulated rats showed that biliary excretion of the unmodified conjugate is the primary route of elimination. Treatment- and time-dependent phosphorylation of H2AX, a marker of DNA damage downstream of topoisomerase 1 inhibition, verified the on-target activity of the payload cleaved from VIP236 in vivo. Treatment with VIP236 resulted in long-lasting tumor regression in subcutaneous patient-derived xenograft (PDX) models from patients with non-small-cell lung, colon, and renal cancer as well as in two orthotopic metastatic triple-negative breast cancer PDX models. In these models, a significant reduction of brain and lung metastases also was observed. Full article

(This article belongs to the Section Cancer Therapy)

► Show Figures

Figure 1

14 pages, 5112 KiB

Open AccessArticle

A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury

by Jun Liu, David C. Yang, Jun Zhang, Ssu-Wei Hsu, Robert H. Weiss and Ching-Hsien Chen

Int. J. Mol. Sci. 2021, 22(24), 13304; https://doi.org/10.3390/ijms222413304 - 10 Dec 2021

Cited by 6 | Viewed by 3667

Abstract

The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)

► Show Figures

Figure 1

Search Results (5)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI

Saved Queries

Search Filter Reset All

Years

Feature Papers

Subjects

Journals

Article Types

Countries / Regions

Search Results (5)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI