Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

Roca, Hernán; Jones, Jennifer A.; Purica, Marta; Weidner, Savannah; Koh, Amy J.; Kuo, Robert; Wilkinson, John E.; Wang, Yugang; Daignault‐Newton, Stephanie; Pienta, Kenneth J.; Morgan, Todd M.; Keller, Evan T.; Nör, Jacques E.; Shea, Lonnie D.; McCauley, Laurie K.

doi:10.1172/jci92466

Cited by 104 publications

(114 citation statements)

References 64 publications

(73 reference statements)

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…CXCL5 levels were significantly increased in the serum of nasopharyngeal carcinoma patients than the healthy group [27]. The levels of CXCL5 in the serum of patients with metastatic prostate cancer were higher than patients with primary prostate cancer or controls [66]. But not all patients had high CXCL5 levels in their blood or tumor tissues.…”

Section: Cxcl5 As a Potential Prognostic Biomarkermentioning

confidence: 84%

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target

Zhang

Wang

Sun

et al. 2020

Cancer Communications

126

View full text Add to dashboard Cite

The components of the tumor microenvironment (TME) in solid tumors, especially chemokines, are currently attracting much attention from scientists. C-X-C motif chemokine ligand 5 (CXCL5) is one of the important chemokines in TME. Overexpression of CXCL5 is closely related to the survival time, recurrence and metastasis of cancer patients. In TME, CXCL5 binds to its receptors, such as C-X-C motif chemokine receptor 2 (CXCR2), to participate in the recruitment of immune cells and promote angiogenesis, tumor growth, and metastasis. The CXCL5/CXCR2 axis can act as a bridge between tumor cells and host cells in TME. Blocking the transmission of CXCL5/CXCR2 signals can increase the sensitivity and effectiveness of immunotherapy and slow down tumor progression. CXCL5 and CXCR2 are also regarded as biomarkers for predicting prognosis and molecular targets for customizing the treatment. In this review, we summarized the current literature regarding the biological functions and clinical significance of CXCL5/CXCR2 axis in TME. The possibility to use CXCL5 and CXCR2 as potential prognostic biomarkers and therapeutic targets in cancer is also discussed

show abstract

Section: Cxcl5 As a Potential Prognostic Biomarkermentioning

confidence: 84%

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target

Zhang

Wang

Sun

et al. 2020

Cancer Communications

126

View full text Add to dashboard Cite

show abstract

“…Both low-dose aspirin and AT-SPMs inhibit experimental primary tumor growth and metastasis by stimulating the clearance of therapy-generated tumor cell debris. Given that traditional cancer therapeutics (e.g., chemotherapy and radiation) induce inflammation and generate tumor cell debris (23)(24)(25), aspirin-triggered lipid autacoids that stimulate endogenous inflammation-clearing (resolution) mechanisms may offer a novel therapeutic approach to harness aspirin's anti-cancer activity while avoiding the toxicity of aspirin.…”

mentioning

confidence: 99%

Aspirin-triggered proresolving mediators stimulate resolution in cancer

Gilligan

Gartung

Sulciner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

113

111

View full text Add to dashboard Cite

Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA 4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity. metabolomics | eicosanoids | resolvins | inflammation | metastasis M ore than 80 million aspirin tablets are consumed every year (1). Epidemiologic evidence suggests that the nonsteroidal anti-inflammatory drug (NSAID) aspirin reduces the risk and incidence of cancer and also prolongs survival when administered postdiagnosis (2). While initial studies have focused on colorectal cancers, low-dose aspirin has also demonstrated consistent antitumor activity in other cancers, including lung, breast, prostate, and metastatic cancers (3,4). Studies have also identified survival and chemopreventive benefits of low-dose aspirin following cytotoxic therapy (e.g., radiation, chemotherapy) or surgical tumor resection (5, 6). Compelling evidence of aspirin's anticancer activity stems from patients receiving low-dose aspirin for cardioprevention, in which a substantial fraction (20-30%) benefits from a decrease in cancer incidence (7). In contrast, several studies show that neither nonaspirin NSAIDs nor acetaminophen are associated with a reduced risk of cancer or chemopreventive activity (8,9). While the known anti-inflammatory activity of aspirin offers a generic rationale, the unique antitumor mechanisms of aspirin compared with other NSAIDs remain poorly understood. Importantly, the use of low-dose aspirin in cancer patients is limited by adverse side effects, such as gastrointestinal bleeding and hemorrhagic stroke, that necessitate hospitalization (10).The study of anti-inflammatory mechanisms in cancer has traditionally focused on the suppression of proinflammatory mediators, such as cytokines, eicosanoids, and enzymes (2). Cycloo...

show abstract

“…Therefore, we studied 182 macrophages both to explore their prevalence and phenotype in bone metastases of PCa 183 and to examine their potential involvement in the regulation of SULF1 and HSPG2 184 expression in desmoplastic bone marrow stoma. In the patient specimens we tested, previous studies showed that CD206 + macrophages are prevalent in prostate tumors in 190 the bone of mice [41,42]. 191 Here we report that the up-regulation of SULF1 and HSPG2 transcripts in CAFs by 192 M2-like macrophages.…”

mentioning

confidence: 60%

SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models

Costa

Lewis

Truong

et al. 2020

Preprint

View full text Add to dashboard Cite

Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2 ) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1's role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs.February 26, 2020 1/21 87 measurement is not possible. Instead, we quantified the transcript levels we detected in 88 each cell population using Imaris software, as described in Materials and Methods. 89Quantification of the SULF1 mRNA shows that approximately 95% of the signal is 90 confined to αSMA + activated fibroblasts, and is nearly undetected in E-cad + tumor 91 February 26, 2020 3/21

show abstract

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

Cited by 104 publications

References 64 publications

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target

Aspirin-triggered proresolving mediators stimulate resolution in cancer

SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models

Contact Info

Product

Resources

About