Models of Renal Cell Carcinoma Used to Investigate Molecular Mechanisms and Develop New Therapeutics

Shapiro, Daniel D.; Virumbrales-Muñoz, María; Beebe, David J.; Abel, E. Jason

doi:10.3389/fonc.2022.871252

Cited by 14 publications

(13 citation statements)

References 118 publications

(208 reference statements)

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“…While the overall trend of multiple comparisons showed coherence with no statistical significance, genetic alterations of CDKN2A/CDKN2B were associated with the aggressive, sarcomatoid patterns of RCC with a stringent significance at 0.05 for CDKN2A and lower down to 0.01 for CDKN2B . Moreover, our findings are consistent with recent reports that showed genetic alterations of CDKN2A/CDKN2B are associated with aggressive forms of RCC and are common in sarcomatoid RCC [ [38] , [39] , [40] , [41] ]. We believe the number of samples is sufficient for our statistical analyses, but we also acknowledge that future study is needed to add to the body of knowledge about the role of CDKN2A/CDKN2B in the establishment of RCC and the applications of CDKN2A/CDKN2B mutation analysis in clinical practice.…”

Section: Discussionsupporting

confidence: 93%

Genetic study of the CDKN2A and CDKN2B genes in renal cell carcinoma patients

Kiatprungvech,

Sangkum,

Malinee

et al. 2024

Practical Laboratory Medicine

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Section: Discussionsupporting

confidence: 93%

Genetic study of the CDKN2A and CDKN2B genes in renal cell carcinoma patients

Kiatprungvech,

Sangkum,

Malinee

et al. 2024

Practical Laboratory Medicine

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“…In general, cell lines are prone to genetic instability during prolonged culture, deviating from their initial phenotypes and losing key tumor characteristics. In conventional cultures, cells lack the tumor microenvironment and dynamic interactions with different cellular components 29 . Most cell lines were isolated from aggressive tumor types and selected for their proliferative nature in culture, poorly representing different tumor types.…”

Section: Introductionmentioning

confidence: 99%

Integrating tumor and healthy epithelium in a micro-physiology multi-compartment approach to study renal cell carcinoma pathophysiology

Somova,

Simm,

Padmyastuti

et al. 2024

Sci Rep

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The advent of micro-physiological systems (MPS) in biomedical research has enabled the introduction of more complex and relevant physiological into in vitro models. The recreation of complex morphological features in three-dimensional environments can recapitulate otherwise absent dynamic interactions in conventional models. In this study we developed an advanced in vitro Renal Cell Carcinoma (RCC) that mimics the interplay between healthy and malignant renal tissue. Based on the TissUse Humimic platform our model combines healthy renal proximal tubule epithelial cells (RPTEC) and RCC. Co-culturing reconstructed RPTEC tubules with RCC spheroids in a closed micro-perfused circuit resulted in significant phenotypical changes to the tubules. Expression of immune factors revealed that interleukin-8 (IL-8) and tumor necrosis factor-alfa (TNF-α) were upregulated in the non-malignant cells while neutrophil gelatinase-associated lipocalin (NGAL) was downregulated in both RCC and RPTEC. Metabolic analysis showed that RCC prompted a shift in the energy production of RPTEC tubules, inducing glycolysis, in a metabolic adaptation that likely supports RCC growth and immunogenicity. In contrast, RCC maintained stable metabolic activity, emphasizing their resilience to external factors. RNA-seq and biological process analysis of primary RTPTEC tubules demonstrated that the 3D tubular architecture and MPS conditions reverted cells to a predominant oxidative phosphorylate state, a departure from the glycolytic metabolism observed in 2D culture. This dynamic RCC co-culture model, approximates the physiology of healthy renal tubules to that of RCC, providing new insights into tumor-host interactions. Our approach can show that an RCC-MPS can expand the complexity and scope of pathophysiology and biomarker studies in kidney cancer research.

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“…Clear cell renal cell carcinoma (ccRCC), representing about 75% of RCC cases, exhibits nests of malignant epithelial cells with clear cytoplasm surrounded by an extensive, arborizing vasculature ( Heidegger et al, 2019 ). Sporadic ccRCCs in humans often harbor inactivating mutations in the VHL tumor suppressor gene, leading to continuous stabilization of hypoxia-inducible transcription factors HIF-1α and HIF-2α ( Shapiro et al, 2022 ). This results in metabolic reprogramming toward aerobic glycolysis and the secretion of factors, including VEGFA, that foster angiogenesis.…”

Section: Current Microphysiological Systems Of ‘Cold’ Tumorsmentioning

confidence: 99%

Microphysiological systems as models for immunologically ‘cold’ tumors

Gaebler,

Hachey,

Hughes

2024

Front. Cell Dev. Biol.

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The tumor microenvironment (TME) is a diverse milieu of cells including cancerous and non-cancerous cells such as fibroblasts, pericytes, endothelial cells and immune cells. The intricate cellular interactions within the TME hold a central role in shaping the dynamics of cancer progression, influencing pivotal aspects such as tumor initiation, growth, invasion, response to therapeutic interventions, and the emergence of drug resistance. In immunologically ‘cold’ tumors, the TME is marked by a scarcity of infiltrating immune cells, limited antigen presentation in the absence of potent immune-stimulating signals, and an abundance of immunosuppressive factors. While strategies targeting the TME as a therapeutic avenue in ‘cold’ tumors have emerged, there is a pressing need for novel approaches that faithfully replicate the complex cellular and non-cellular interactions in order to develop targeted therapies that can effectively stimulate immune responses and improve therapeutic outcomes in patients. Microfluidic devices offer distinct advantages over traditional in vitro 3D co-culture models and in vivo animal models, as they better recapitulate key characteristics of the TME and allow for precise, controlled insights into the dynamic interplay between various immune, stromal and cancerous cell types at any timepoint. This review aims to underscore the pivotal role of microfluidic systems in advancing our understanding of the TME and presents current microfluidic model systems that aim to dissect tumor-stromal, tumor-immune and immune-stromal cellular interactions in various ‘cold’ tumors. Understanding the intricacies of the TME in ‘cold’ tumors is crucial for devising effective targeted therapies to reinvigorate immune responses and overcome the challenges of current immunotherapy approaches.

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Models of Renal Cell Carcinoma Used to Investigate Molecular Mechanisms and Develop New Therapeutics

Cited by 14 publications

References 118 publications

Genetic study of the CDKN2A and CDKN2B genes in renal cell carcinoma patients

Genetic study of the CDKN2A and CDKN2B genes in renal cell carcinoma patients

Integrating tumor and healthy epithelium in a micro-physiology multi-compartment approach to study renal cell carcinoma pathophysiology

Microphysiological systems as models for immunologically ‘cold’ tumors

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