Cellular and physical microenvironments regulate the aggressiveness and sunitinib chemosensitivity of clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is the most predominant type of kidney cancer in adults and is responsible for approximately 85% of clinical cases. The tumor-specific microenvironment includes both cellular and physical factors, and it regulates the homeostasis and function of cancer cells. Perirenal adipose tissue and tumor-associated macrophages are the major cellular components of the RCC microenvironment. The RCC microvasculature network generates interstitial fluid flow, which is the movement of fluid through the extracellular compartments of tissues. This fluid flow is a specific physical characteristic of the microenvironment of RCC. We hypothesized that there may be an interaction between the cellular and physical microenvironments and that these two factors may play an important role in regulating the behavior of RCC. To elucidate the effects of adipose tissue, macrophages and fluid flow stimulation on RCC and to investigate the relationships between these factors, we used a collagen gel culture method to generate cancer-stroma interactions and a gyratory shaker to create fluid flow stimulation. Adipose-related cells, monocytes and fluid flow influenced the proliferative potential and invasive capacity of RCC cells. Extracellular signal-regulated kinase and p38 signaling were regulated either synergistically or independently by both fluid flow and cellular interactions between RCC and adipose tissue fragments or macrophages. Fluid flow stimulation synergistically enhanced the anti-proliferative effect of sunitinib on RCC cells, but macrophages abolished the synergistic anti-proliferative effect related to fluid flow stimulation. In conclusion, we established a reconstructed model to investigate the cellular and physical microenvironments of RCC in vitro. Our alternative culture model may provide a promising tool for further therapeutic investigations into many types of cancer. This article is protected by copyright. All rights reserved.

The Journal of pathology. 2021 Jan 29 [Epub ahead of print]

Kei Nagase, Takashi Akutagawa, Mihoko Rikitake-Yamamoto, Sayuri Morito, Maki Futamata, Shohei Tobu, Mitsuru Noguchi, Shuji Toda, Shigehisa Aoki

Division of Pathology, Department of Pathology and Microbiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan., Department of Urology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.