Imaging transforming growth factor-β signaling dynamics and therapeutic response in breast cancer bone metastasis

Korpal, Manav; Yan, Jun; Lü, Xin; Xu, Shansheng; Lerit, Dorothy A.; Kang, Yibin

doi:10.1038/nm.1943

Cited by 203 publications

(175 citation statements)

References 32 publications

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“…46 Moreover, zoledronate displays antiangiogenic activity and can decrease the secretion of immunosuppressive (TGF-b, FGF-b and metalloproteinases) and proinflammatory (IL-1b, IL-6 and IL-8) factors. 42,[47][48][49][50] In a previous clinical trial designed to evaluate phosphoantigen administration in B-cell malignancies, a correlation was observed between the in vivo expansion of Vc9Vd2 T cells and the objective antitumor response. 18 An adoptive transfer immunotherapy assay has also been conducted in metastatic renal cell carcinoma by Kobayashi et al 21 and in lung carcinoma by Nakajima et al 51 These studies found that autologous Vc9Vd2 T cells are well tolerated and induce an antitumor effect.…”

Section: Discussionmentioning

confidence: 99%

Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

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Cabillic

Toutirais

et al. 2011

Intl Journal of Cancer

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Epithelial ovarian cancer (EOC) usually spreads into the peritoneal cavity, thereby providing an opportunity for intraperitoneal adoptive immunotherapy with Vc9Vd2 T lymphocytes, a T cell subpopulation endowed with high lytic properties against tumor cells. However, previous studies have reported that Vc9Vd2 T cells fail to expand from peripheral blood mononuclear cells in one-third of patients with cancer. Here, from a cohort of 37 patients with EOC, a multiple correspondence analysis identified three populations, one of which was not suitable for Vc9Vd2 T-cell adoptive therapy. Interestingly, the ineligible patients were identified based on the frequency of Vc9Vd2 T cells in their peripheral blood and the patients' age. The average time to tumor recurrence was also found to be significantly different between the three populations, suggesting that the innate immune response is involved in EOC prognosis. A dramatic decrease in the lytic properties of Vc9Vd2 T cells occurred following incubation with ascitic supernatant and was found to be associated with reduced perforin/granzyme degranulation. Prostaglandin E2, but not IL-6, IL-10, VEGF or TGF-b, showed immunosuppressive effects in Vc9Vd2 T cells. Interestingly, our results emphasize that pretreating ovarian tumor cells with zoledronate partially reverses the immunosuppressive effects of ovarian cancer-associated ascites and restores a high level of lytic activity. These data sustain that optimal Vc9Vd2 T-cell adoptive immunotherapy previously requires counteracting the tumor immunosuppressive microenvironment. Altogether, our findings provide a rationale for clinically evaluating Vc9Vd2 T-cell adoptive immunotherapy with intraperitoneal carcinomatosis presensitization by zoledronate in patients with EOC.Epithelial ovarian cancer (EOC) is the fifth most frequent cancer among women and the fourth most common cause of cancer-related deaths among women.1 More than 70% of patients are diagnosed when the cancer has spread beyond the ovaries, and these patients have low median survival rates.2 The prognosis is poor, with a 5-year survival rate of only 30%, and the rate is less than 10% for patients with bulky residual disease remaining after surgery and chemotherapy, which emphasizes the need for innovative treatments.3 The inflammatory microenvironment of ovarian carcinomas prevents the maturation of myeloid cells, favors regulatory T-cell development and restrains the cytotoxic activity of effector T lymphocytes, leading to the escape of the tumor from the immune system. 4 Thus, research is ongoing to develop innovative approaches aimed at stimulating the immune system. 5 The preferential spread pattern of EOC in the peritoneal cavity offers an excellent opportunity for the regional administration of adoptive T-cell therapy.2 Some pilot trials have shown the feasibility of and promising

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Section: Discussionmentioning

confidence: 99%

Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

Lavoué

Cabillic

Toutirais

et al. 2011

Intl Journal of Cancer

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“…Upon reaching the bone microenvironment, cancer cells activate the differentiation of bone-degrading osteoclasts either directly or indirectly by promoting the increased production of osteoclastogenesis cytokines by osteoblasts [2]. Differentiated osteoclasts dissolve mineralized bone, leading to the release of a large compendium of growth factors and cytokines, such as PDGF, FGF, and IGFs and TGF-β [2][3][4], from the bone matrix, which in turn promote the growth of and continued pro-osteolytic signaling by cancer cells [5]. Notably, communication between cancer cells and bone stromal cells is typically mediated via secreted proteins.…”

Section: Introductionmentioning

confidence: 99%

Global secretome analysis identifies novel mediators of bone metastasis

et al. 2012

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Bone is the one of the most common sites of distant metastasis of solid tumors. Secreted proteins are known to influence pathological interactions between metastatic cancer cells and the bone stroma. To comprehensively profile secreted proteins associated with bone metastasis, we used quantitative and non-quantitative mass spectrometry to globally analyze the secretomes of nine cell lines of varying bone metastatic ability from multiple species and cancer types. By comparing the secretomes of parental cells and their bone metastatic derivatives, we identified the secreted proteins that were uniquely associated with bone metastasis in these cell lines. We then incorporated bioinformatic analyses of large clinical metastasis datasets to obtain a list of candidate novel bone metastasis proteins of several functional classes that were strongly associated with both clinical and experimental bone metastasis. Functional validation of selected proteins indicated that in vivo bone metastasis can be promoted by high expression of (1) the salivary cystatins CST1, CST2, and CST4; (2) the plasminogen activators PLAT and PLAU; or (3) the collagen functionality proteins PLOD2 and COL6A1. Overall, our study has uncovered several new secreted mediators of bone metastasis and therefore demonstrated that secretome analysis is a powerful method for identification of novel biomarkers and candidate therapeutic targets.

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“…Tumor-produced factors such as parathyroid hormone-related protein (PTHrP), interleukin-11 (IL-11), IL-6, and IL-8 stimulate bone resorption to release and activate growth factors housed in the mineralized bone matrix. Bone-derived TGF-b promotes osteolysis by stimulating tumor production of osteolytic factors, and alters the bone microenvironment to further increase osteoclastic bone resorption and inhibit bone formation Korpal et al 2009;Mohammad et al 2009). These tumor-bone interactions result in a feed-forward cycle to promote tumor growth in bone.…”

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confidence: 99%

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Guise

2009

Genes Dev.

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Bone metastases are the most common skeletal complication of malignancy. Tumor cells disrupt normal bone remodeling to promote bone destruction and its associated morbidity. In the August 15, 2009, issue of Genes & Development, Lu and colleagues (pp. 1882-1894) propose a novel molecular mechanism by which tumor-produced metalloproteinases release epidermal growth factor (EGF) ligands to activate the central osteoclastogenic pathway receptor activator of NF-kB ligand (RANKL) to promote breast cancer osteolysis. This work has important therapeutic applications that may quickly translate to more effective treatment for bone metastases.Bone metastases are common in breast, prostate, and lung cancer, and are associated with significant morbidity. Unique aspects of the bone microenvironment-such as mineralized bone matrix, which houses immobilized growth factors, bone-destroying osteoclasts, and boneforming osteoblasts-make it a fertile soil for these cancers to grow. Significant insight into the molecular mechanisms responsible for the proclivity of tumors to metastasize and grow in bone has been gleaned in recent years from mouse models and clinical studies. Bone destruction mediated by solid tumor metastases to bone, particularly in breast cancer, is driven by tumor stimulation of osteoclastic bone resorption. Collective evidence supports the notion that effective therapy for bone metastases should target both the tumor and the bone microenvironment. Indeed, bisphosphonate therapy to block osteoclastic bone resorption, used in conjunction with standard anti-cancer treatments, reduces bone pain, pathologic fracture, and hypercalcemia associated with bone metastases from all tumor types. However, regression and cure of bone metastases have yet to be achieved with the current therapeutic armamentarium. Thus, a better understanding of the molecular mechanisms responsible for this devastating skeletal complication of malignancy is required to develop more effective therapy, with the eventual goal of curing and preventing bone metastases. In the August 15, 2009, issue of Genes & Development, Lu et al. (2009) bring the field closer to this goal. They describe an autocrine/paracrine signaling cascade triggered by metalloproteinases-matrix metalloproteinase-1 (MMP-1) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)-and cleavage of epidermal growth factor (EGF) ligands to reduce the ratio of osteoblast-produced receptor activator of NF-kB ligand (RANKL) to osteoprotegerin (OPG) to favor osteoclastogenesis and promote breast cancer osteolysis. These studies, described herein, have important implications for new applications of standard cancer therapy that could result in more effective treatment for bone metastases. Bone metastases: clinical features and current therapyCertain solid tumors-such as breast, prostate, and lung cancer-have a propensity to metastasize to bone to cause bone pain, fracture, hypercalcemia, and paralysis. This morbidity is great: Up to 75% of advanced breast and prostate c...

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Imaging transforming growth factor-β signaling dynamics and therapeutic response in breast cancer bone metastasis

Cited by 203 publications

References 32 publications

Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

Global secretome analysis identifies novel mediators of bone metastasis

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

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