Abstract
Stromal cell populations in the tumor microenvironment (TME) play a critical role in the oncogenesis and metastasis of renal cell carcinoma. In this study, we found that there are α-smooth muscle actin positive (α-SMA (+)) cells in the stroma of clear cell renal cell carcinoma (ccRCC) tissues, and their numbers are significantly associated with poor survival in ccRCC patients. Interleukin 6 (IL-6) is a critical diver that induces α-SMA (+) cells in ccRCC tissues via promotion of epithelial to mesenchymal transition (EMT) and stimulates migration and invasion in ccRCC. Peritumoral CD4+ T cells are the main source of IL-6 in ccRCC tissues. In addition to biochemical factors, mechanical compression within tumors affects tumor cell behavior. Tumors grown in a confined space exhibit intratumoral compressive stress and, with sufficient pressure, stress-stimulated migration of cancer cells. Moreover, a combination of IL-6 secreted by CD4+ T cells and growth-induced solid stress further contributes to the regulation of cancer cell morphogenesis, EMT and acquisition of a stemness phenotype. The effects in the combination group were driven by the Akt/GSK-3β/β-catenin signaling pathway, and deregulation of β-catenin expression was predictive of poor outcome in ccRCC patients. Notably, the expression of a cancer stem cell marker, CD44, was correlated with T stage, high Fuhrman grade and metastasis in ccRCC. These data provide evidence for new stress-reducing and IL-6 targeting strategies in cancer therapy.
Highlights
Clear cell renal cell carcinoma is the most common form of kidney cancer, and comprises more than 75% of these malignancies.[1] ccRCC is a highly radio- and chemo-resistant cancer grossly characterized by cell heterogeneity and hypervascularity.[2]Recently, the role of the tumor microenvironment (TME) has attracted increasing attention from researchers.[3,4] Stromal cells in the surrounding microenvironment are recruited to tumors, and these accelerate growth at the primary site and facilitate its metastatics to distant organs.[5]
Suggested that compressive stress enhances epithelialmesenchymal transition (EMT) and high CD44 expression was correlated with Fuhrman grade stemness induced by Interleukin 6 (IL-6) via the Akt/GSK-3β/β-catenin signaling (Figure 6g, top right, P = 0.002, respectively) and metastasis in pathway and CD44 is a marker of advanced-stage in patients ccRCC tissues (Figure 6g, bottom left, P = 0.003)
Based on our self-designed ‘TME PCR Array’ and immunohistochemistry, we found that in the stroma of high Fuhrman grade ccRCC, there are more α-SMA (+) cells compared with low Fuhrman grade ccRCC and these are correlated with progression and survival in ccRCC patients
Summary
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, and comprises more than 75% of these malignancies.[1] ccRCC is a highly radio- and chemo-resistant cancer grossly characterized by cell heterogeneity and hypervascularity.[2]. The role of the tumor microenvironment (TME) has attracted increasing attention from researchers.[3,4] Stromal cells in the surrounding microenvironment are recruited to tumors, and these accelerate growth at the primary site and facilitate its metastatics to distant organs.[5] Several elements of the TME promote an adaptive escape system, called the epithelialmesenchymal transition (EMT). EMT leads to dramatic changes in the mechanical properties of cells, several studies have focused on how mechanical factors affect EMT, such as fluid shear stress and ECM stiffness.[11,12,13] Recently, a role for growth-induced solid stress in tumor pathogenesis has been identified. We combined IL-6 with growth-induced stress for tumor cells and found that solid stress enhanced EMT and stem-like properties induced by IL-6 in ccRCC via the Akt/GSK-3β/β-catenin signaling pathway
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