Stromal Fibroblasts Counteract the Caveolin-1-Dependent Radiation Response of LNCaP Prostate Carcinoma Cells.

Alina Wittka,Verena Jendrossek,Julia Ketteler,Carsten Herskind,Lars Borgards,Patrick Maier,Diana Klein

doi:10.3389/fonc.2022.802482

Abstract

In prostate cancer (PCa), a characteristic stromal–epithelial redistribution of the membrane protein caveolin 1 (CAV1) occurs upon tumor progression, where a gain of CAV1 in the malignant epithelial cells is accompanied by a loss of CAV1 in the tumor stroma, both facts that were correlated with higher Gleason scores, poor prognosis, and pronounced resistance to therapy particularly to radiotherapy (RT). However, it needs to be clarified whether inhibiting the CAV1 gain in the malignant prostate epithelium or limiting the loss of stromal CAV1 would be the better choice for improving PCa therapy, particularly for improving the response to RT; or whether ideally both processes need to be targeted. Concerning the first assumption, we investigated the RT response of LNCaP PCa cells following overexpression of different CAV1 mutants. While CAV1 overexpression generally caused an increased epithelial-to-mesenchymal phenotype in respective LNCaP cells, effects that were accompanied by increasing levels of the 5′-AMP-activated protein kinase (AMPK), a master regulator of cellular homeostasis, only wildtype CAV1 was able to increase the three-dimensional growth of LNCaP spheroids, particularly following RT. Both effects could be limited by an additional treatment with the SRC inhibitor dasatinib, finally resulting in radiosensitization. Using co-cultured (CAV1-expressing) fibroblasts as an approximation to the in vivo situation of early PCa it could be revealed that RT itself caused an activated, more tumor-promoting phenotype of stromal fibroblats with an increased an increased metabolic potential, that could not be limited by combined dasatinib treatment. Thus, targeting fibroblasts and/or limiting fibroblast activation, potentially by limiting the loss of stromal CAV1 seems to be absolute for inhibiting the resistance-promoting CAV1-dependent signals of the tumor stroma.

Highlights

Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide with nearly 1.5 million new cases estimated for 2020 and nearly 400,000 burden related deaths [1, 2]
In order to gain insight into the latter fact, LNCaP prostate cancer (PCa) cells with low endogenous caveolin 1 (CAV1) expression levels were transduced with different CAV1 mutants and respective cultures stably overexpressing the introduced CAV1 variants were generated (Figure 1)
At advanced tumor stages the gain in epithelial CAV1 was associated with increased invasion and metastasis and therapy resistance, to RT

Summary

Introduction

Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide with nearly 1.5 million new cases estimated for 2020 and nearly 400,000 burden related deaths [1, 2]. A loss of stromal, fibroblastic CAV1 could be observed, which correlated with tumor progression and therapy resistance, and may be suited as a prognostic marker. Activated fibroblasts, termed cancerassociated fibroblasts (CAF), were shown to foster therapy resistance of malignant epithelial cells in a CAV1-dependent manner [12,13,14,15]. A re-distribution of CAV1 was further observed in malignant prostate epithelial cells upon progression of xenograft tumors grown from CAV1-deficient PCa cells, an effect that coincided with increased radiation resistance. CAV1-deficient fibroblasts were shown to foster RT resistance of PCa cells by allocating CAV1-dependent apoptosis inhibiting proteins to the tumor cells, e.g., the p53-inducible cell survival factor TRIAP1 (TP53-regulated inhibitor of apoptosis 1, known as p53CSV) [13]

Methods

Results

Conclusion