Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases

Cook, Leah M.; Shay, Gemma; Aruajo, Arturo; Lynch, Conor C.

doi:10.1007/s10555-014-9494-4

Cited by 76 publications

(58 citation statements)

References 140 publications

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“…However, while bisphosphonates delay the time to first skeletal related event (SRE) such as pathological fracture, they do not significantly extend overall survival for the majority of patients with bone metastases (7,8). Other microenvironmental targeted therapies such as RANKL based inhibitors and radium-223 have improved time to first SRE and overall survival for patients with bone metastatic disease respectively (9). Thus, there is strong rationale for further definition of the molecular circuitry underpinning cancer-bone communication so as to generate new therapies that can cure the disease or significantly improve overall survival rates.…”

Section: Introductionmentioning

confidence: 99%

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

Tauro

Shay

Sansil

et al. 2017

Molecular Cancer Therapeutics

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Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor or host derived MMP-2 contributes to breast cancer growth and does so by processing substrates including type I collagen and transforming growth factorβ (TGFβ) latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. In vitro, BMMPIs impacted the viability of breast cancer cell lines and osteoclast precursors but not osteoblasts. In vivo, we demonstrated using two bone metastatic models (PyMT-R221A and 4T1) that BMMPI treatment significantly reduced tumor growth and tumor associated bone destruction. Additionally, BMMPIs are superior in promoting tumor apoptosis compared to the standard of care bisphosphonate, zoledronate. We demonstrated MMP-2 selective inhibition in the bone microenvironment using specific and broad spectrum MMP probes. Further, compared to zoledronate, BMMPI treated mice had significantly lower levels of TGFβ signaling and MMP generated type I collagen carboxy-terminal (ICTP) fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. We posit that BMMPIs could be easily translated to the clinical setting for the treatment of bone metastases given the well-tolerated nature of bisphosphonates.

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Section: Introductionmentioning

confidence: 99%

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

Tauro

Shay

Sansil

et al. 2017

Molecular Cancer Therapeutics

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“…1 Transforming growth factor b (TGFb) plays pivotal roles in controlling cell proliferation, apoptosis, and the final fate of metazoan cells. 2,3 In malignancies, TGFb is initially a tumor suppressor, since it inhibits cell proliferation and induces apoptosis, but at later stages of tumor progression, it is often produced at high levels by tumor and stromal cells and promotes tumor progression.…”

Section: Introductionmentioning

confidence: 99%

TRAF6 promotes TGFβ-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGFβ type I receptor

et al. 2015

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Transforming growth factor b (TGFb) can act either as a tumor promoter or a tumor suppressor in a contextdependent manner. High levels of TGFb are found in prostate cancer tissues and correlate with poor patient prognosis. We recently identified a novel TGFb-regulated signaling cascade in which TGFb type I receptor (TbRI) is activated by the E3 ligase TNF-receptor-associated factor 6 (TRAF6) via the Lys63-linked polyubiquitination of TbRI. TRAF6 also contributes to activation of TNF-a-converting enzyme and presenilin-1, resulting in the proteolytic cleavage of TbRI and releasing the intracellular domain of TbRI, which is translocated to the nucleus to promote tumor invasiveness. In this report, we provide evidence that Lys178 of TbRI is polyubiquitinated by TRAF6. Moreover, our data suggest that TRAF6-mediated Lys63-linked ubiquitination of the TbRI intracellular domain is a prerequisite for TGFb regulation of mRNA for cyclin D1 (CCND1), expression, as well as for the regulation of other genes controlling the cell cycle, differentiation, and invasiveness of prostate cancer cells.

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“…Cook's group proposed that the production of CXCL16 by cancer cells recruits MSCs into tumor sites. Tumor-derived CXCL16 interacts with its receptor CXCR6, resulting MSCs to convert into cancer-associated fibroblasts (CAFs), which were found to be critical for promoting tumor growth, epithelial to mesenchymal transition (EMT), and metastasis to bone [32,33]. It has also been reported that osteoclast activities are very important for homing, growth, and development of tumor cell in bone [8,34].…”

Section: Discussionmentioning

confidence: 99%

MEK inhibitor diminishes nasopharyngeal carcinoma (NPC) cell growth and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions

et al. 2015

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Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. NPC frequently metastasizes to the bone in advanced patients resulting in high mortality. The molecular mechanisms for NPC development and cancer-induced bone lesions are unclear. In this study, we firstly determined chemokine receptor CCR2 and CXCR6 expressions in clinical specimens and CNE2, SUNE1, CNE1, and HK1 cell lines. Then, we measured chemokine CCL2 and CXCL16 production in these NPC cell lines by ELISA. Expression levels of these chemokines and their receptors were observed to positively correlate with tumor aggressiveness. Furthermore, U0126 (MEK inhibitor) was used to treat these NPC cell lines. CCL2 and CXCL16 expression levels and cell proliferation were significantly inhibited by U0126 in a dose- and time-dependent manner. Finally, we collected conditioned medium (CM) from NPC cell cultures in the presence of U0126 treatment. When mouse bone marrow non-adherent cells were treated with the CM, the numbers of multinucleated osteoclast formation were dramatically diminished. These results indicate that MEK inhibitor diminishes NPC cell proliferation and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions. This study provides novel therapeutic targets such as CCL2/CCR2 and CXCL16/CXCR6 for advanced NPC patients.

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Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases

Cited by 76 publications

References 140 publications

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

TRAF6 promotes TGFβ-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGFβ type I receptor

MEK inhibitor diminishes nasopharyngeal carcinoma (NPC) cell growth and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions

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