Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer

Wikström, Pernilla; Stattin, Pär; Franck-Lissbrant, Ingela; Damber, Jan‐Erik; Bergh, Anders

doi:10.1002/(sici)1097-0045(19980915)37:1<19::aid-pros4>3.0.co;2-3

Cited by 281 publications

(192 citation statements)

References 43 publications

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“…7,43 The expression of tumor growth factor-␤ is increased in human prostate cancers 44 and in our animal model (our own unpublished observations). Tumor growth factor-␤ also regulates HAS 1 to 3.…”

Section: Discussionmentioning

confidence: 67%

Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome

Josefsson

Adamo

Hammarsten

et al. 2011

The American Journal of Pathology

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Our objective was to investigate whether the presence of a tumor increases hyaluronan (HA) levels in surrounding prostate tissues and whether this extratumoral HA influences tumor growth and outcome. From a series of 287 men diagnosed with prostate cancer at transurethral resection and followed up with watchful waiting, tissue microarrays were constructed, stained, and scored for HA. A high HA staining score in the tumor stroma or in nonmalignant prostate tissue stroma were both associated positively with higher Gleason score and larger tumor volume, and was associated with a poor outcome. HA staining score was not an independent marker for outcome (multivariate Cox, with Gleason score, tumor volume, stage, and HA variables). In an orthotopic rat prostate cancer model, hyaluronic acid synthase-1 mRNA levels and HA staining were increased in normal prostate tissue surrounding prostate cancer. Orthotopic prostate cancer growth was increased by intraprostatic injection of HA. In conclusion, cancer in the prostate apparently stimulates HA synthesis both in tumor stroma and in the surrounding normal tissue. This promoted tumor growth and was associated with an unfavorable outcome. (Am J Pathol

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Section: Discussionmentioning

confidence: 67%

Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome

Josefsson

Adamo

Hammarsten

et al. 2011

The American Journal of Pathology

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“…Consistent with this notion, increased TGFb1 expression by tumor cells correlated with tumor progression in non-small cell lung carcinoma (NSCLC), colorectal cancer, prostate cancer, and gastric carcinoma [13][14][15][16]. Additionally, intense TGFb staining has also been positively correlated with metastasis in breast carcinoma, prostate cancer, and colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

Roles of TGFβ in metastasis

2008

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The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGFβ can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFβ signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFβ therapies are currently being developed and tested in preclinical studies. However, targeting TGFβ carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFβ has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFβ inhibitors for clinical use will require a deeper understanding of TGFβ signaling, its consequences, and the contexts in which it acts.

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“…In particular, local resident fibroblasts are thought to be activated via tumor cell‐derived soluble factors of which transforming growth factor beta 1 (TGFβ1) is the most characterized and activates prostatic fibroblasts to a CAF‐like phenotype in vitro and in vivo 2, 8. Notably, circulating TGFβ1 levels positively correlate with PCa risk, rapid disease progression and poor outcome 11, 12…”

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confidence: 99%

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

Sampson

Brunner

Weber

et al. 2018

Intl Journal of Cancer

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Carcinoma‐associated fibroblasts (CAFs) play a key onco‐supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)‐producing enzyme NADPH oxidase 4 (Nox4) is essential for TGFβ1‐mediated activation of primary prostate human fibroblasts to a CAF‐like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine‐mediated PCa‐relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri‐tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGFβ protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF‐associated marker expression and migration of TGFβ1‐activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA‐mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGFβ1‐driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGFβ1‐activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGFβ1 as conditioned media from PCa cell lines endogenously secreting high TGFβ1 levels induced fibroblast activation in a stromal Nox4‐ and TGFβ receptor‐dependent manner. Importantly, GKT137831 also attenuated PCa cell‐driven fibroblast activation. Collectively, these findings suggest the TGFβ‐Nox4 signaling axis is a key interface to dysregulated reciprocal stromal–epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal‐targeted approach to complement current PCa treatment modalities.

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Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer

Cited by 281 publications

References 43 publications

Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome

Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome

Roles of TGFβ in metastasis

Inhibition of Nox4‐dependent ROS signaling attenuates prostate fibroblast activation and abrogates stromal‐mediated protumorigenic interactions

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