Future Treatment of Bone Metastases

Lipton, Allan

doi:10.1158/1078-0432.ccr-06-1157

Cited by 67 publications

(44 citation statements)

References 22 publications

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“…(5,26,27) Osteolysis by activated osteoclasts leads to the release of growth factors stored in the bone matrix. (8) Because TGFβ is abundant in the bone matrix, the critical role of TGFβ has been indicated in the development of bone metastasis.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor β derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activation‐associated osteolysis in the bone microenvironment

Sato¹,

Futakuchi²,

Ogawa³

et al. 2008

Cancer Science

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Metastatic prostate tumors in the bone microenvironment stimulate bone resorption, resulting in release of growth factors from the bone matrix that play important roles in tumor growth and osteoclast induction. Transforming growth factor β β β β (TGFβ β β β) is one of the most abundantly stored cytokines in bone matrix, regulating diverse biological activities. Here we evaluate its involvement in prostate tumor growth in the bone microenvironment, comparing with tumor growth in the subcutaneous microenvironment as a control. Rat prostate tumors were transplanted onto the cranial bone and into the subcutis of F344 male rats. Tumor cell proliferation, apoptosis, and TGFβ β β β signal transduction were compared between the tumor-bone interface and the tumorsubcutaneous interface. Effects of TGFβ β β β on osteoclast differentiation were also evaluated in vitro. Inhibitory effects of TGFβ β β β receptor 1 antisense oligonucleotide on TGFβ β β β signaling, osteolysis, osteoblasts, and tumor growth were examined in vivo. Osteolytic changes were extensively observed at the tumor-bone interface, where the TGFβ β β β level, TGFβ β β β signal transduction, and tumor cell proliferation were higher than at the tumor-subcutaneous interface. In vitro treatment with receptor activator of nuclear factor-κ κ κ κB ligand induced osteoclast differentiation of bone marrow stromal cells, and additional exposure to TGFβ β β β exerted promotive effects on osteoclast induction. Intratumoral injection of TGFβ β β β receptor 1 antisense oligonucleotide significantly reduced TGFβ β β β signal transduction, osteolysis, induction of osteoclast and osteoblast, and tumor cell proliferation. Thus, we experimentally show that TGFβ β β β derived from bone matrix promotes cell proliferation of rat prostate cancer and osteoclast activation-associated osteolysis in the bone microenvironment. (Cancer Sci 2008; 99: 316-323) B one metastases are the most critical complications with advanced prostate cancer, resulting in severe pain, morbidity, and often mortality.(1,2) Conventional therapies do not allow a curative outcome for prostate cancer bone metastasis, (3,4) and elucidation of molecular mechanisms that regulate prostate tumor growth in the bone microenvironment is essential for development of new therapeutic approaches to prevent bone metastasis.Once cancer cells reach the bone microenvironment, a reciprocal cellular interaction between tumor and bone stromal cells was observed. (5,6) This interaction between the tumor and bone stromal cells has been commonly referred to as a "vicious cycle", whereby tumor and stromal cells in the bone secrete several factors beneficial to each other. (7)(8)(9) In the vicious cycle, metastatic prostate tumor cells in the bone microenvironment produce cytokines that stimulate osteoclastic bone resorption.This then results in the release of growth factors such as TGFβ, (10) insulin-like growth factors, (10) and bone morphological proteins (11) from the bone matrix. In bone metastatic sites, prostate tumor cells, o...

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Section: Discussionmentioning

confidence: 99%

Transforming growth factor β derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activation‐associated osteolysis in the bone microenvironment

Sato¹,

Futakuchi²,

Ogawa³

et al. 2008

Cancer Science

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“…Detailed consideration of the range of established and investigational strategies for treating bone metastasis in malignancy is outside the scope of this review, although these have been amply reviewed elsewhere [59,60]. However, of note in terms of an established class of bone-preserving agents are the bisphosphonates.…”

Section: Other Signal-blocking Strategies In Bone Metastatic Prostatementioning

confidence: 99%

Src as a therapeutic target in men with prostate cancer and bone metastases

Saad

2009

BJU International

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and bone-signalling processes involved in prostate tumour progression, driving proliferation, survival, migration and transition to androgen-independent growth. It is also intimately involved in positively regulating osteoclast physiology. As such, this molecule represents an attractive target for managing progressing prostate cancer. Encouraging results have been obtained in preclinical and clinical studies using Src inhibitors like AZD0530 and dasatinib. Both compounds reduced markers of bone resorption, in patients with cancer and those with advanced castration-resistant prostate cancer, respectively. Moreover, because Src is central to many mechanisms thought to be responsible for the development of castration resistance, adding Src inhibitors to a treatment regimen might reverse this phenomenon. As a result, many Src inhibitors are in preclinical development. This review explores Src inhibition as a strategy for managing bone metastasis in prostate cancer, with a particular focus on targeting the critical osteoclastic response. Other emerging and novel approaches are also considered.

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“…Bone-derived TGFb and PDGF also promote tumor progression in bone marrow (4). CCL2 is known as another chemokine critical for bone metastatic mechanism in various cancers (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…A variety of therapeutics targeting these molecules has been developed for treating bone metastasis (4). However, their subjects are mostly postmetastasis events, but not premetastatic state.…”

Section: Introductionmentioning

confidence: 99%

Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction

et al. 2013

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Bone metastasis greatly deteriorates the quality of life in patients with cancer. Although mechanisms have been widely investigated, the relationship between cancer bone metastasis and antitumor immunity in the host has been much less studied. Here, we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatinlike glycoprotein secreted by Snail þ tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis-in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45 À ALCAM þ cells derived from bone marrow. CD45 À ALCAM þ cells induced bone metastasis de novo, but they also generated CD8 low T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interferencemediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM þ cells and CD8 low T cells. These effects were accompanied by heightened antitumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM þ cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in patients with cancer. Cancer Res; 73(20); 6185-93. Ó2013 AACR.

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Future Treatment of Bone Metastases

Cited by 67 publications

References 22 publications

Transforming growth factor β derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activation‐associated osteolysis in the bone microenvironment

Transforming growth factor β derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activation‐associated osteolysis in the bone microenvironment

Src as a therapeutic target in men with prostate cancer and bone metastases

Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction

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