Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1

Research output: Contribution to journalArticle

Raúl Catena, Nandita Bhattacharya, Tina El Rayes, Suming Wang, Hyejin Choi, Dingcheng Gao, Seongho Ryu, Natasha Joshi, Diane Bielenberg, Sharrell B. Lee, Svein A. Haukaas, Karsten Gravdal, Ole J. Halvorsen, Lars A. Akslen, Randolph S. Watnick, Vivek Mittal

Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1+ bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. Significance: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow-derived Gr1+ myeloid cells. A 5-amino acid peptide with Tsp-1-inducing activity was identified as a therapeutic agent against metastatic cancer.

Original languageEnglish
Pages (from-to)578-589
Number of pages12
JournalCancer Discovery
Volume3
Issue number5
DOIs
StatePublished - May 1 2013

PMID: 23633432

PMCID: PMC3672408

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Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. / Catena, Raúl; Bhattacharya, Nandita; El Rayes, Tina; Wang, Suming; Choi, Hyejin; Gao, Dingcheng; Ryu, Seongho; Joshi, Natasha; Bielenberg, Diane; Lee, Sharrell B.; Haukaas, Svein A.; Gravdal, Karsten; Halvorsen, Ole J.; Akslen, Lars A.; Watnick, Randolph S.; Mittal, Vivek.

In: Cancer Discovery, Vol. 3, No. 5, 01.05.2013, p. 578-589.

Research output: Contribution to journalArticle

Harvard

Catena, R, Bhattacharya, N, El Rayes, T, Wang, S, Choi, H, Gao, D, Ryu, S, Joshi, N, Bielenberg, D, Lee, SB, Haukaas, SA, Gravdal, K, Halvorsen, OJ, Akslen, LA, Watnick, RS & Mittal, V 2013, 'Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1' Cancer Discovery, vol. 3, no. 5, pp. 578-589. https://doi.org/10.1158/2159-8290.CD-12-0476

APA

Catena, R., Bhattacharya, N., El Rayes, T., Wang, S., Choi, H., Gao, D., ... Mittal, V. (2013). Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discovery, 3(5), 578-589. https://doi.org/10.1158/2159-8290.CD-12-0476

Vancouver

Catena R, Bhattacharya N, El Rayes T, Wang S, Choi H, Gao D et al. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discovery. 2013 May 1;3(5):578-589. https://doi.org/10.1158/2159-8290.CD-12-0476

Author

Catena, Raúl ; Bhattacharya, Nandita ; El Rayes, Tina ; Wang, Suming ; Choi, Hyejin ; Gao, Dingcheng ; Ryu, Seongho ; Joshi, Natasha ; Bielenberg, Diane ; Lee, Sharrell B. ; Haukaas, Svein A. ; Gravdal, Karsten ; Halvorsen, Ole J. ; Akslen, Lars A. ; Watnick, Randolph S. ; Mittal, Vivek. / Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. In: Cancer Discovery. 2013 ; Vol. 3, No. 5. pp. 578-589.

BibTeX

@article{39d733d488e7461fbad0008642142e37,
title = "Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1",
abstract = "Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1+ bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. Significance: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow-derived Gr1+ myeloid cells. A 5-amino acid peptide with Tsp-1-inducing activity was identified as a therapeutic agent against metastatic cancer.",
author = "Ra{\'u}l Catena and Nandita Bhattacharya and {El Rayes}, Tina and Suming Wang and Hyejin Choi and Dingcheng Gao and Seongho Ryu and Natasha Joshi and Diane Bielenberg and Lee, {Sharrell B.} and Haukaas, {Svein A.} and Karsten Gravdal and Halvorsen, {Ole J.} and Akslen, {Lars A.} and Watnick, {Randolph S.} and Vivek Mittal",
year = "2013",
month = "5",
day = "1",
doi = "10.1158/2159-8290.CD-12-0476",
language = "English",
volume = "3",
pages = "578--589",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

RIS

TY - JOUR

T1 - Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1

AU - Catena, Raúl

AU - Bhattacharya, Nandita

AU - El Rayes, Tina

AU - Wang, Suming

AU - Choi, Hyejin

AU - Gao, Dingcheng

AU - Ryu, Seongho

AU - Joshi, Natasha

AU - Bielenberg, Diane

AU - Lee, Sharrell B.

AU - Haukaas, Svein A.

AU - Gravdal, Karsten

AU - Halvorsen, Ole J.

AU - Akslen, Lars A.

AU - Watnick, Randolph S.

AU - Mittal, Vivek

PY - 2013/5/1

Y1 - 2013/5/1

N2 - Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1+ bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. Significance: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow-derived Gr1+ myeloid cells. A 5-amino acid peptide with Tsp-1-inducing activity was identified as a therapeutic agent against metastatic cancer.

AB - Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow-derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1+ bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. Significance: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow-derived Gr1+ myeloid cells. A 5-amino acid peptide with Tsp-1-inducing activity was identified as a therapeutic agent against metastatic cancer.

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UR - http://www.scopus.com/inward/citedby.url?scp=84877602573&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-12-0476

DO - 10.1158/2159-8290.CD-12-0476

M3 - Article

VL - 3

SP - 578

EP - 589

JO - Cancer Discovery

T2 - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 5

ER -

ID: 2644788