Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches 2.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 14840

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Guest Editor
Instituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, 90127 Palermo, Italy
Interests: clinical nephrology; renal disease; nephrology urinary; infections; nephrotic syndrome; pediatric nephrology
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Guest Editor
Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
Interests: renal cell carcinoma; pathology; molecular pathology; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Renal cell carcinoma is a complex disease comprised of a variety of histological subtypes. The most common histological subtype is clear cell renal cell carcinoma (ccRCC), which accounts for 70–80% of kidney cancer. Recent diagnostic and therapeutic advances are improving the survival rate of kidney cancer patients. The loss of tumor suppressor genes and activation of oncogenes allow tumors to reprogram the pathways. A large number of biomarkers have been proposed for predicting RCC recurrence. Some molecular-targeted therapies, such as tyrosine kinase inhibitors, mTOR inhibitors, and immunotherapies, have dramatically improved the outcome of RCCs. Ultrasonography is the most frequently used imaging modality for the initial diagnosis of renal masses, but a multimodality imaging approach is routinely performed in RCC. The medical treatment of RCC has greatly changed in recent years, thanks to new information acquired on the molecular pathogenesis and of its histology. However, acquired drug resistance and treatment for a prognostically unfavorable subgroup of ccRCCs and other histological subtypes remain a major challenge. Novel biomarkers to predict outcomes, drug responses, and a novel therapeutic target are highly desirable.

This Special Issue of Biomedicines focuses on recent discoveries on clinicopathological, physiological, and molecular approaches to the diagnosis, classification, and novel multidisciplinary treatment. Considering the complexity of the molecular biological background of each histological subtype of renal cell carcinoma, we welcome contributions aimed at both major and emerging histological subtypes of renal cell carcinoma.

Dr. Silvio Maringhini
Dr. Riuko Ohashi
Guest Editors

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Keywords

  • renal cell carcinoma
  • pathology
  • physiology
  • diagnosis
  • multimodal treatment
  • drug resistance
  • biomarkers

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Published Papers (7 papers)

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Research

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19 pages, 4395 KiB  
Article
Differential Activation of NRF2 Signaling Pathway in Renal-Cell Carcinoma Caki Cell Lines
by Naomi L. Hitefield, Stephen Mackay, Lauren E. Hays, Shimin Chen, Ian O. Oduor, Dean A. Troyer and Julius O. Nyalwidhe
Biomedicines 2023, 11(4), 1010; https://doi.org/10.3390/biomedicines11041010 - 24 Mar 2023
Viewed by 1616
Abstract
Renal-cell carcinoma (RCC) is a heterogeneous disease consisting of several subtypes based on specific genomic profiles and histological and clinical characteristics. The subtype with the highest prevalence is clear-cell RCC (ccRCC), next is papillary RCC (pRCC), and then chromophobe RCC (chRCC). The ccRCC [...] Read more.
Renal-cell carcinoma (RCC) is a heterogeneous disease consisting of several subtypes based on specific genomic profiles and histological and clinical characteristics. The subtype with the highest prevalence is clear-cell RCC (ccRCC), next is papillary RCC (pRCC), and then chromophobe RCC (chRCC). The ccRCC cell lines are further subdivided into prognostic expression-based subtypes ccA or ccB. This heterogeneity necessitates the development, availability, and utilization of cell line models with the correct disease phenotypic characteristics for RCC research. In this study, we focused on characterizing proteomic differences between the Caki-1 and Caki-2 cell lines that are commonly used in ccRCC research. Both cells are primarily defined as human ccRCC cell lines. Caki-1 cell lines are metastatic, harboring wild-type VHL, whereas Caki-2 are considered as the primary ccRCC cell lines expressing wild-type von Hippel–Lindau protein (pVHL). Here, we performed a comprehensive comparative proteomic analysis of Caki-1 and Caki-2 cells using tandem mass-tag reagents together with liquid chromatography mass spectrometry (LC/MS) for the identification and quantitation of proteins in the two cell lines. Differential regulation of a subset of the proteins identified was validated using orthogonal methods including western blot, q-PCR, and immunofluorescence assays. Integrative bioinformatic analysis identifies the activation/inhibition of specific molecular pathways, upstream regulators, and causal networks that are uniquely regulated and associated with the two cell lines and RCC subtypes, and potentially the disease stage. Altogether, we have identified multiple molecular pathways, including NRF2 signaling, which is the most significantly activated pathway in Caki-2 versus Caki-1 cells. Some of the differentially regulated molecules and signaling pathways could serve as potential diagnostic and prognostic biomarkers and therapeutic targets amongst ccRCC subtypes. Full article
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14 pages, 2087 KiB  
Article
TFEB Rearranged Renal Cell Carcinoma: Pathological and Molecular Characterization of 10 Cases, with Novel Clinical Implications: A Single Center 10-Year Experience
by Ai-Xiang Wang, Tai Tian, Li-Bo Liu, Feng Yang, Hui-Ying He and Li-Qun Zhou
Biomedicines 2023, 11(2), 245; https://doi.org/10.3390/biomedicines11020245 - 18 Jan 2023
Cited by 1 | Viewed by 2334
Abstract
To report our experience with the cases of TFEB rearranged RCC, with particular attention to the clinicopathological, immunohistochemical and molecular features of these tumors and to their predictive markers of response to therapy. We have retrieved the archives of 9749 renal cell carcinomas [...] Read more.
To report our experience with the cases of TFEB rearranged RCC, with particular attention to the clinicopathological, immunohistochemical and molecular features of these tumors and to their predictive markers of response to therapy. We have retrieved the archives of 9749 renal cell carcinomas in the Institute of Urology, Peking University and found 96 rearranged RCCs between 2013 and 2022. Among these renal tumors, ten cases meet the morphologic, immunohistochemical and FISH characterization for TFEB rearranged RCC. The 10 patients’ mean and median age is 34.9 and 34 years, respectively (range 23–55 years old), and the male to female ratio is 1:1.5. Macroscopically, these tumors generally have a round shape and clear boundary. They present with variegated, grayish yellow and grayish brown cut surface. The average maximum diameter of the tumor is 8.5 cm and the median 7.7 (ranged from 3.4 to 16) cm. Microscopically, the tumor is surrounded by a thick local discontinuous pseudocapsule. All tumors exhibit two types of cells: voluminous, clear and eosinophilic cytoplasm cells arranged in solid sheet, tubular growth pattern with local cystic changes, and papillary, pseudopapillary and compact nested structures are also seen in a few cases. Non-neoplastic renal tubules are entrapped in the tumor. A biphasic “rosette-like” pattern, psammomatous calcifications, cytoplasmic vacuolization, multinucleated giant cells and rhabdomyoid phenotype can be observed in some tumors. A few tumors may be accompanied by significant pigmentation or hemorrhage and necrosis. The nucleoli are equivalent to the WHO/ISUP grades 2–4. All tumors are moderately to strongly positive for Melan-A, TFEB, Vimentin and SDHB, and negative for CK7, CAIX, CD117, EMA, SMA, Desmin and Actin. CK20 and CK8/18 are weakly positive. In addition, AE1/AE3, P504s, HMB45 and CD10 are weakly moderately positive. TFE3 is moderately expressed in half of the cases. PAX8 can be negative, weakly positive or moderately-strongly positive. The therapy predictive marker for PD-L1 (SP263) is moderately to strongly positive membranous staining in all cases. All ten tumors demonstrate a medium frequency of split TFEB fluorescent signals ranging from 30 to 50% (mean 38%). In two tumors, the coincidence of the TFEB gene copy number gains are observed (3–5 fluorescent signals per neoplastic nuclei). Follow-up is available for all patients, ranging from 4 to 108 months (mean 44.8 and median 43.4 months). All patients are alive, without tumor recurrences or metastases. We described a group of TFEB rearranged RCC identified retrospectively in a large comprehensive Grade III hospital in China. The incidence rate was about 10.4% of rearranged RCCs and 0.1% of all the RCCs that were received in our lab during the ten-year period. The gross morphology, histological features, and immunohistochemistry of TFEB rearranged RCC overlapped with other types of RCC such as TFE3 rearranged RCC, eosinophilic cystic solid RCC, or epithelioid angiomyolipoma, making the differential diagnosis challenging. The diagnosis was based on TFEB fluorescence in situ hybridization. At present, most of the cases reported in the literature have an indolent clinical behavior, and only a small number of reported cases are aggressive. For this small subset of aggressive cases, it is not clear how to plan treatment strategies, or which predictive markers could be used to assess upfront responses to therapies. Between the possible options, immunotherapy currently seems a promising strategy, worthy of further exploration. In conclusion, we described a group of TFEB rearranged RCC identified in a large, comprehensive Grade III hospital in China, in the last 10 years. Full article
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11 pages, 640 KiB  
Article
Efficacy and Safety of Cabozantinib in Patients with Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study
by Koji Iinuma, Risa Tomioka-Inagawa, Koji Kameyama, Tomoki Taniguchi, Kei Kawada, Takashi Ishida, Shingo Nagai, Torai Enomoto, Shota Ueda, Makoto Kawase, Shinichi Takeuchi, Kota Kawase, Daiki Kato, Manabu Takai, Keita Nakane and Takuya Koie
Biomedicines 2022, 10(12), 3172; https://doi.org/10.3390/biomedicines10123172 - 07 Dec 2022
Cited by 3 | Viewed by 1555
Abstract
A multicenter retrospective study was conducted to evaluate the efficacy and safety of cabozantinib in patients with advanced or metastatic renal cell carcinoma (mRCC). We enrolled 53 patients with mRCC who received cabozantinib at eight institutions in Japan. The primary endpoint was overall [...] Read more.
A multicenter retrospective study was conducted to evaluate the efficacy and safety of cabozantinib in patients with advanced or metastatic renal cell carcinoma (mRCC). We enrolled 53 patients with mRCC who received cabozantinib at eight institutions in Japan. The primary endpoint was overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). In addition, we analyzed prognostic factors in patients with mRCC treated with cabozantinib. The median follow-up period was 8 months, and the median OS was 20.0 months. The ORR and DCR were 39.6% and 83.0%, respectively. The median PFS was 11.0 months. PFS was significantly shorter in patients previously treated with at least two tyrosine kinase inhibitors and in those with C-reactive protein (CRP) ≥ 1.27 mg/dL (p = 0.021 and p = 0.029, respectively). Adverse events of any grade and grades ≥3 occurred in 42 (79.2%) and 10 (18.9%) patients, respectively. Cabozantinib is a useful treatment option for patients with mRCC and may benefit from earlier use. In this study, CRP ≥ 1.27 mg/dL is a poor prognostic factor in patients treated with cabozantinib, and careful follow-up may be required in treating patients with high CRP. Full article
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Review

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14 pages, 961 KiB  
Review
Current Approaches in Surgical and Immunotherapy-Based Management of Renal Cell Carcinoma with Tumor Thrombus
by Marina M. Tabbara, Javier González, Melanie Martucci and Gaetano Ciancio
Biomedicines 2023, 11(1), 204; https://doi.org/10.3390/biomedicines11010204 - 13 Jan 2023
Cited by 7 | Viewed by 2435
Abstract
Renal cell carcinoma (RCC) accounts for 2–3% of all malignant disease in adults, with 30% of RCC diagnosed at locally advanced or metastatic stages of disease. A form of locally advanced disease is the tumor thrombus (TT), which commonly grows from the intrarenal [...] Read more.
Renal cell carcinoma (RCC) accounts for 2–3% of all malignant disease in adults, with 30% of RCC diagnosed at locally advanced or metastatic stages of disease. A form of locally advanced disease is the tumor thrombus (TT), which commonly grows from the intrarenal veins, through the main renal vein, and up the inferior vena cava (IVC), and rarely, into the right cardiac chambers. Advances in all areas of medicine have allowed increased understanding of the underlying biology of these tumors and improved preoperative staging. Although the development of several novel system agents, including several clinical trials utilizing immune checkpoint inhibitors and combination therapies, has been shown to lower perioperative morbidity and increase post-operative recurrence-free and progression-free survival, surgery remains the mainstay of therapy to achieve a cure. In this review, we provide a description of specific surgical approaches and techniques used to minimize intra- and post-operative complications during radical nephrectomy and tumor thrombectomy of RCC with TT extension of various levels. Additionally, we provide an in-depth review of the major developments in neoadjuvant and adjuvant immunotherapy-based treatment and the impact of ongoing and recently completed clinical trials on the surgical treatment of advanced RCC. Full article
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14 pages, 622 KiB  
Review
Diagnostic and Prognostic Biomarkers in Renal Clear Cell Carcinoma
by Chaston Weaver, Khaled Bin Satter, Katherine P. Richardson, Lynn K. H. Tran, Paul M. H. Tran and Sharad Purohit
Biomedicines 2022, 10(11), 2953; https://doi.org/10.3390/biomedicines10112953 - 17 Nov 2022
Cited by 12 | Viewed by 2359
Abstract
Renal clear cell carcinoma (ccRCC) comprises over 75% of all renal tumors and arises in the epithelial cells of the proximal convoluted tubule. Molecularly ccRCC is characterized by copy number alterations (CNAs) such as the loss of chromosome 3p and VHL inactivation. Additional [...] Read more.
Renal clear cell carcinoma (ccRCC) comprises over 75% of all renal tumors and arises in the epithelial cells of the proximal convoluted tubule. Molecularly ccRCC is characterized by copy number alterations (CNAs) such as the loss of chromosome 3p and VHL inactivation. Additional driver mutations (SETD2, PBRM1, BAP1, and others) promote genomic instability and tumor cell metastasis through the dysregulation of various metabolic and immune-response pathways. Many researchers identified mutation, gene expression, and proteomic signatures for early diagnosis and prognostics for ccRCC. Despite a tremendous influx of data regarding DNA alterations, gene expression, and protein expression, the incorporation of these analyses for diagnosis and prognosis of RCC into the clinical application has not been implemented yet. In this review, we focused on the molecular changes associated with ccRCC development, along with gene expression and protein signatures, to emphasize the utilization of these molecular profiles in clinical practice. These findings, in the context of machine learning and precision medicine, may help to overcome some of the barriers encountered for implementing molecular profiles of tumors into the diagnosis and treatment of ccRCC. Full article
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19 pages, 1046 KiB  
Review
Contemporary Drug Therapy for Renal Cell Carcinoma—Evidence Accumulation and Histological Implications in Treatment Strategy
by Kazutoshi Yamana, Riuko Ohashi and Yoshihiko Tomita
Biomedicines 2022, 10(11), 2840; https://doi.org/10.3390/biomedicines10112840 - 07 Nov 2022
Cited by 3 | Viewed by 1792
Abstract
Renal cell carcinoma (RCC) is a heterogeneous disease comprising a variety of histological subtypes. Approximately 70–80% of RCC cases are clear cell carcinoma (ccRCC), while the remaining subtypes constitute non-clear cell carcinoma (nccRCC). The medical treatment of RCC has greatly changed in recent [...] Read more.
Renal cell carcinoma (RCC) is a heterogeneous disease comprising a variety of histological subtypes. Approximately 70–80% of RCC cases are clear cell carcinoma (ccRCC), while the remaining subtypes constitute non-clear cell carcinoma (nccRCC). The medical treatment of RCC has greatly changed in recent years through advances in molecularly targeted therapies and immunotherapies. Most of the novel systemic therapies currently available have been approved based on ccRCC clinical trial data. nccRCC can be subdivided into more than 40 histological subtypes that have distinct clinical, histomorphological, immunohistochemical, and molecular features. These entities are listed as emerging in the 2022 World Health Organization classification. The diagnosis of nccRCC and treatments based on cancer histology and biology remain challenging due to the disease’s rarity. We reviewed clinical trials focused on recent discoveries regarding clinicopathological features. Full article
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Other

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11 pages, 9181 KiB  
Opinion
Current Knowledge and Prospects for Renal Hemangioblastoma and Renal Cell Carcinoma with Hemangioblastoma-like Features
by Fumiyoshi Kojima, Fidele Y. Musangile, Ibu Matsuzaki, Kenji Yorita, Naoto Kuroda, Yoji Nagashima and Shin-ichi Murata
Biomedicines 2023, 11(5), 1467; https://doi.org/10.3390/biomedicines11051467 - 17 May 2023
Cited by 1 | Viewed by 1451
Abstract
Tumors exhibiting histopathological findings similar to those of hemangioblastoma of the central nervous system (CNS-HB) rarely develop in the kidneys. Currently, renal hemangioblastoma (RHB) is considered analogous to CNS-HB; however, they differ in gross appearance, as well as immunohistochemical and molecular findings. In [...] Read more.
Tumors exhibiting histopathological findings similar to those of hemangioblastoma of the central nervous system (CNS-HB) rarely develop in the kidneys. Currently, renal hemangioblastoma (RHB) is considered analogous to CNS-HB; however, they differ in gross appearance, as well as immunohistochemical and molecular findings. In contrast, some renal cell carcinomas reportedly comprise distinct, clear cell renal cell carcinoma (CCRCC)- and hemangioblastoma (HB)-like areas. Initially, renal cell carcinomas with HB-like features (RCC-HBs) were considered a morphological variant of CCRCC owing to their diverse histological findings. However, the immunohistochemical and molecular findings of RCC-HBs suggest that RCC-HB is distinct from CCRCC. Additionally, one of the RCC-HBs had a focal leiomyomatous stroma and TSC2 variant, suggesting that RCC-HB and RCC with fibromyomatous stroma (RCC-FMS) might belong to the same disease entity. Therefore, we comprehensively reviewed the clinical, pathological, and molecular features of RHB, RCC-HB, and the related tumors and discussed the similarities, differences, and relationships between them. We believe that our review would serve as a foundation for further investigation on elucidating the relationship between CNS-HB, RHB, RCC-HB, and RCC-FMS. Full article
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