Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

Kerr, Bethany A.; Harris, Koran S.; Shi, Lihong; Willey, Jeffrey S.; Soto-Pantoja, David R.; Byzova, Tatiana V.

doi:10.1101/2020.02.11.943860

Cited by 13 publications

(14 citation statements)

References 60 publications

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“…Downregulation of the TGFβ pathway may block communication between the primary tumour and bone microenvironment, and thus may block the formation of the premetastatic niche in skeleton tissues; however, this would result in no alteration in the growth of the primary tumour. It seems that the TGFβ pathway is a promising anti-metastatic molecular target and the concentration of TGFβ in platelets might represent a potential biomarker of cancer aggressiveness [ 88 ].…”

Section: Platelet Tgfβ In a Cancermentioning

confidence: 99%

Blood Platelets as an Important but Underrated Circulating Source of TGFβ

Karolczak¹,

Watała²

2021

IJMS

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When treating diseases related primarily to tissue remodeling and fibrosis, it is desirable to regulate TGFβ concentration and modulate its biological effects. The highest cellular concentrations of TGFβ are found in platelets, with about 40% of all TGFβ found in peripheral blood plasma being secreted by them. Therefore, an understanding of the mechanisms of TGFβ secretion from platelets may be of key importance for medicine. Unfortunately, despite the finding that platelets are an important regulator of TGFβ levels, little research has been carried out into the development of platelet-directed therapies that might modulate the TGFβ-dependent processes. Nevertheless, there are some very encouraging reports suggesting that platelet TGFβ may be specifically involved in cardiovascular diseases, liver fibrosis, tumour metastasis, cerebral malaria and in the regulation of inflammatory cell functions. The purpose of this review is to briefly summarize these few, extremely encouraging reports to indicate the state of current knowledge in this topic. It also attempts to better characterize the influence of TGFβ on platelet activation and reactivity, and its shaping of the roles of blood platelets in haemostasis and thrombosis.

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Section: Platelet Tgfβ In a Cancermentioning

confidence: 99%

Blood Platelets as an Important but Underrated Circulating Source of TGFβ

Karolczak¹,

Watała²

2021

IJMS

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“…Our prior studies demonstrated that subcutaneous RM1 tumor growth induced bone formation and that platelets governed this pre-metastatic communication with the bone microenvironment ( 7 , 29 ). To examine whether deletion of bone marrow-derived SCF would alter the bone microenvironment, bone sections from tumor-bearing mice were stained for tartrate-resistant acid phosphatase (TRAP) positive osteoclasts to determine osteoclast number and measure bone histomorphometry.…”

Section: Resultsmentioning

confidence: 99%

Bone Marrow-Derived Stem Cell Factor Regulates Prostate Cancer-Induced Shifts in Pre-Metastatic Niche Composition

et al. 2022

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Skeletal metastasis is the leading cause of morbidity and mortality in prostate cancer, with 80% of advanced prostate cancer patients developing bone metastases. Before metastasis, bone remodeling occurs, stimulating pre-metastatic niche formation and bone turnover, and platelets govern this process. Stem cell factor (SCF, Kit Ligand) is increased in advanced prostate cancer patient platelet releasates. Further, SCF and its receptor, CD117/c-kit, correlate with metastatic prostate cancer severity. We hypothesized that bone-derived SCF plays an important role in prostate cancer tumor communication with the bone inducing pre-metastatic niche formation. We generated two cell-specific SCF knockout mouse models deleting SCF in either mature osteoblasts or megakaryocytes and platelets. Using two syngeneic androgen-insensitive murine prostate cancer cell lines, RM1 (Ras and Myc co-activation) and mPC3 (Pten and Trp53 deletion), we examined the role of bone marrow-derived SCF in primary tumor growth and bone microenvironment alterations. Platelet-derived SCF was required for mPC3, but not RM1, tumor growth, while osteoblast-derived SCF played no role in tumor size in either cell line. While exogenous SCF induced proangiogenic protein secretion by RM1 and mPC3 prostate cancer cells, no significant changes in tumor angiogenesis were measured by immunohistochemistry. Like our previous studies, tumor-induced bone formation occurred in mice bearing RM1 or mPC3 neoplasms, demonstrated by bone histomorphometry. RM1 tumor-bearing osteoblast SCF knockout mice did not display tumor-induced bone formation. Bone stromal cell composition analysis by flow cytometry showed significant shifts in hematopoietic stem cell (HSC), mesenchymal stem cell (MSC), and osteoblast cell percentages in mice bearing RM1 or mPC3 tumors. There were no significant changes in the percentage of macrophages, osteoclasts, or osteocytes. Our study demonstrates that megakaryocyte/platelet-derived SCF regulates primary mPC3 tumor growth, while SCF originating from osteoblasts plays a role in bone marrow-derived progenitor cell composition and pre-metastatic niche formation. Further, we show that both the source of SCF and the genetic profile of prostate cancer determine the effects of SCF. Thus, targeting the SCF/CD117 signaling axis with tyrosine kinase inhibitors could affect primary prostate carcinomas or play a role in reducing bone metastasis dependent on the gene deletions or mutations driving the patients’ prostate cancer.

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“…The percentages of Sca-1 positive and endomucin vasculature, markers for hematopoietic stem/tumorigenic cells and blood vessels, respectively, within the bones of mice with ER+ E0771/Bone derived tumors were significantly increased when compared with TN derived tumors. Previous studies across multiple cancer types have demonstrated that tumors can modulate the premetastatic bone microenvironment to become a more hospitable environment by increasing hematopoietic stem cells and vasculature [44][45][46]. Thus, the numbers of potential colonization niches were increased in mice with ER+ E0771/Bone tumors.…”

Section: Discussionmentioning

confidence: 97%

A Novel Model of Estrogen Receptor-Positive Breast Cancer Bone Metastasis with Antiestrogen Responsiveness

Langsten

Shi

Wilson

et al. 2021

Preprint

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Most women diagnosed with breast cancer (BC) have estrogen receptor alpha positive (ER+) disease. ER+ BC preferentially metastasizes to bone; at which time it is considered incurable. Treatments for bone metastasis have not advanced in decades, in part due to a lack of appropriate ER+ BC bone metastasis models. We developed an immunocompetent ER+ BC murine model with spontaneous bone metastasis and antiestrogen responsiveness. To do this, we transduced triple-negative (TN) bone-tropic murine BC cell lines 4T1.2 and E0771/Bone to express ERα. These cells were then injected into the mammary fat pads of Balb/c (n=21) or C57Bl/6 (n=27), respectively. Once tumors established, mice were treated with either the selective estrogen receptor modulator (SERM) tamoxifen (TAM), the selective estrogen receptor degrader (SERD) ICI 182,780 (ICI, Faslodex, fulvestrant), or vehicle control for 21 days. Tumor volumes and weights significantly decreased in the ER+ groups treated with TAM and ICI compared with ER+ vehicle-treated groups. Staining for immune profiles and total RNA sequencing demonstrated modified immune cell infiltration between TN and ER-derived tumors. Approximately 25% of the mice with ER+ 4T1.2 tumors developed metastases to long bones while none of the mice with TN tumors developed metastases. This immunocompetent ER+ 4T1.2 BC model may allow for further exploration of ER+ BC bone metastasis mechanisms and for the development of new therapeutics for women diagnosed with bone metastasis from ER+ BC.

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Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

Cited by 13 publications

References 60 publications

Blood Platelets as an Important but Underrated Circulating Source of TGFβ

Blood Platelets as an Important but Underrated Circulating Source of TGFβ

Bone Marrow-Derived Stem Cell Factor Regulates Prostate Cancer-Induced Shifts in Pre-Metastatic Niche Composition

A Novel Model of Estrogen Receptor-Positive Breast Cancer Bone Metastasis with Antiestrogen Responsiveness

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