Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone

Kobayashi, Aya; Okuda, Hiroshi; Xing, Fei; Pandey, Puspa R.; Watabe, Misako; Hirota, Shigeru; Pai, Sudha K.; Wen, Lei; Fukuda, Koji; Chambers, Christopher B.; Wilber, Andrew; Watabe, Kounosuke

doi:10.1084/jem.20110840

Cited by 355 publications

(291 citation statements)

References 78 publications

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“…Isolation of CSCs-CSCs were isolated by magnetic bead sorting using a magnetic-assisted cell sorting (MACS) separator (Miltenyi Biotec) as described previously (18). PC3mm cells were incubated with the following specific antibodies: anti-CD24-biotin (STEMCELL Technologies), anti-CD44-APC (BioLegend), and anti-CD133-biotin (Miltenyi Biotec).…”

Section: Methodsmentioning

confidence: 99%

“…Bone-To establish a model for dormancy and recurrent growth of prostate cancer, we first prepared CSCs from the PC3mm cell line using the defined cell surface markers CD24 low /CD44 high /CD133 high , as reported previously (18). CSCs were then implanted into mouse tibial bones with a dose by which ϳ50% of tibiae developed overt tumors after 1 month.…”

Section: Isolation Of Paired Prostate Cell Lines As a Model For Dormamentioning

confidence: 99%

“…Bone Stroma-We reported previously that stromal expression of BMP7 induced dormancy by reducing "stemness" and inducing reversible senescence of prostate cancer cells in bone (18). Therefore, we wondered whether it was possible that SPARC up-regulates BMP7 expression in bone stromal cells.…”

Section: Sparc Up-regulates Bmp7 Expression and Secretion Frommentioning

confidence: 99%

“…The activation of bone morphogenetic protein receptors (BMPRs) by BMP7 is known to trigger the downstream signaling cascade (27). We have previously shown that BMPR2 is one of the major receptors associated with dormancy of prostate cancer cells and that BMP7 selectively binds this receptor (18). Therefore, to examine whether the decrease in cancer stemness is mediated through BMPR2, we knocked down BMPR2 in PC3mm .…”

Section: Sparc Up-regulates Bmp7 Expression and Secretion Frommentioning

confidence: 99%

“…Bone stromal cells were reported previously to induce dormancy of cancer cells either through exosome-mediated secretion of inhibitory microRNAs or through secretion of stromal proteins such as TGF␤2 and BMP7 (18,59). BMP7 is known to affect invasion and migration by inhibiting epithelial-to-mesenchymal transition of cancer cells (60,61).…”

Section: Recurrence Dormancymentioning

confidence: 99%

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Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

Sharma

Xing

Yin

et al. 2016

Journal of Biological Chemistry

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Prostate cancer is known to frequently recur in bone; however, how dormant cells switch its phenotype leading to recurrent tumor remains poorly understood. We have isolated two syngeneic cell lines (indolent and aggressive) through in vivo selection by implanting PC3mm stem-like cells into tibial bones. We found that indolent cells retained the dormant phenotype, whereas aggressive cells grew rapidly in bone in vivo, and the growth rates of both cells in culture were similar, suggesting a role of the tumor microenvironment in the regulation of dormancy and recurrence. Indolent cells were found to secrete a high level of secreted protein acidic and rich in cysteine (SPARC), which significantly stimulated the expression of BMP7 in bone marrow stromal cells. The secreted BMP7 then kept cancer cells in a dormant state by inducing senescence, reducing "stemness," and activating dormancy-associated p38 MAPK signaling and p21 expression in cancer cells. Importantly, we found that SPARC was epigenetically silenced in aggressive cells by promoter methylation, but 5-azacytidine treatment reactivated the expression. Furthermore, high SPARC promoter methylation negatively correlated with disease-free survival of prostate cancer patients. We also found that the COX2 inhibitor NS398 down-regulated DNMTs and increased expression of SPARC, which led to tumor growth suppression in bone in vivo. These findings suggest that SPARC plays a key role in maintaining the dormancy of prostate cancer cells in the bone microenvironment.

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Section: Methodsmentioning

confidence: 99%

Section: Isolation Of Paired Prostate Cell Lines As a Model For Dormamentioning

confidence: 99%

Section: Sparc Up-regulates Bmp7 Expression and Secretion Frommentioning

confidence: 99%

Section: Sparc Up-regulates Bmp7 Expression and Secretion Frommentioning

confidence: 99%

Section: Recurrence Dormancymentioning

confidence: 99%

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Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

Sharma

Xing

Yin

et al. 2016

Journal of Biological Chemistry

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Circulating and disseminated tumor cells: harbingers or initiators of metastasis?

2017

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Tumor cells leave the primary tumor and enter the circulation. Once there, they are called circulating tumor cells (CTCs). A fraction of CTCs are capable of entering distant sites and persisting as disseminated tumor cells (DTCs). An even smaller fraction of DTCs are capable of progressing toward metastases. It is known that the DTC microenvironment plays an important role in sustaining their survival, regulating their growth, and conferring resistance to therapy. But we still have much to learn about the nature of these rare cell populations to predict which will progress and what exactly should cause concern for future relapse. Although recent technological advances in our ability to detect and molecularly and functionally characterize CTCs and DTCs promise to unravel this ambiguity, the timing of dissemination and the precise source of CTCs and DTCs profiled will impact the conclusions that can be made from these endeavors. In this review, we discuss the biology of CTCs and DTCs; the technologies to detect, isolate, and profile these cells; and the exceptions we must apply to our understanding of what role these cells play in the metastatic process. We conclude that a greater effort to understand the unique biology of these cells in context will positively impact our ability to use these cells to predict outcome, monitor treatment efficacy, and reveal therapeutically relevant targets to deplete these populations and ultimately prevent metastasis.

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SMAD3/SP1 complex‐mediated constitutive active loop between lncRNA PCAT7 and TGF‐β signaling promotes prostate cancer bone metastasis

Lang

Dai

et al. 2020

Molecular Oncology

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Bone metastasis is associated with cancer‐related death in patients with prostate cancer (PCa). Long noncoding RNAs (lncRNAs) play critical roles in tumor progression of PCa. Nevertheless, the biological function of lncRNAs in PCa bone metastasis remains unclear. PCAT7 was identified as a bone metastasis‐related lncRNA via analyzing TCGA dataset. Meanwhile, PCAT7 was found to be elevated in primary PCa tissues with bone metastasis and associated with bone metastasis status and poor prognosis of patients with PCa. Functionally, our results reveal that PCAT7 overexpression promotes PCa bone metastasis in vivo, as well as migration, invasion, and EMT of PCa cells in vitro; on the contrary, PCAT7 knockdown has an inverse effect. Mechanistically, PCAT7 activates TGF‐β/SMAD signaling by upregulating TGFBR1 expression via sponging miR‐324‐5p. In turn, TGF‐β signaling forms a positive feedback loop with PCAT7 via SMAD3/SP1 complex‐induced PCAT7 upregulation. Finally, the clinical positive correlation between PCAT7 and TGFBR1 and TGF‐β signaling activity, and the negative association with miR‐324‐5p are further demonstrated in PCa tissues and clinical primary PCa cells. This study reveals a novel mechanism that is responsible for the constitutive activation of TGF‐β signaling in PCa bone metastasis, implying that PCAT7 can act as a potential therapeutic target against bone metastasis of PCa via disrupting the constitutive active loop between PCAT7 and TGF‐β signaling.

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Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone

Abstract: BMP7 released by bone marrow stromal cells induces reversible senescence of prostate cancer stem-like cells, and BMPR2 expression inversely correlates with bone metastasis and recurrence in prostate cancer patients.

Cited by 355 publications

References 78 publications

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

Circulating and disseminated tumor cells: harbingers or initiators of metastasis?

SMAD3/SP1 complex‐mediated constitutive active loop between lncRNA PCAT7 and TGF‐β signaling promotes prostate cancer bone metastasis

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