The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells

Russell, Michael; Jamieson, Whitney L.; Dolloff, Nathan G.; Fatatis, Alessandro

doi:10.1038/onc.2008.390

Cited by 42 publications

(57 citation statements)

References 31 publications

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“…The correct penetration of the cardiac wall was established by the appearance of fresh arterial blood in the LuerLok fitting of the hypodermic needle. In addition, blue-fluorescent polystyrene beads (10 μm diameter; Invitrogen, Molecular Probes) were coinjected with cancer cells and their detection in the adrenal glands was utilized to confirm successful inoculation in the blood circulation (51,52). Animals were sacrificed after 72 hours, and adrenal glands and bones were fixed in 4% formalin for 48 hours.…”

Section: Figure 10mentioning

confidence: 99%

“…Sections of each hind leg and soft-tissue organs were transferred on glass slides, stored at -20°C, and examined for cancer cells using a Zeiss AX10 fluorescence microscope connected to a Nuance multispectral imaging system (CRI) with a measurement module included in the analysis software (v. 2.4). Bright field and fluorescence images were acquired with an Olympus DT70 CCD color camera (51,52).…”

Section: Figure 10mentioning

confidence: 99%

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Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells

et al. 2013

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Metabolic reprogramming is an important driver of tumor progression; however, the metabolic regulators of tumor cell motility and metastasis are not understood. Here, we show that tumors maintain energy production under nutrient deprivation through the function of HSP90 chaperones compartmentalized in mitochondria. Using cancer cell lines, we found that mitochondrial HSP90 proteins, including tumor necrosis factor receptor-associated protein-1 (TRAP-1), dampen the activation of the nutrient-sensing AMPK and its substrate UNC-51-like kinase (ULK1), preserve cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from inhibition by the autophagy initiator FIP200. In turn, this results in enhanced tumor cell invasion in low nutrients and metastatic dissemination to bone or liver in disease models in mice. Moreover, we found that phosphorylated ULK1 levels were correlated with shortened overall survival in patients with non-small cell lung cancer. These results demonstrate that mitochondrial HSP90 chaperones, including TRAP-1, overcome metabolic stress and promote tumor cell metastasis by limiting the activation of the nutrient sensor AMPK and preventing autophagy.

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Section: Figure 10mentioning

confidence: 99%

Section: Figure 10mentioning

confidence: 99%

Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells

et al. 2013

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“…Cells were cultured at 37°C and 5% CO 2 in DMEM supplemented with 10% fetal bovine serum (Hyclone) and 0.1% gentamicin (Invitrogen). The PC3-ML cells were engineered to stably express enhanced variant of green fluorescent protein (GFP) by using a lentiviral vector from America Pharma Source (17).…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…This scenario is likely determined by the fact that disseminated cancer cells may benefit from additional trophic support that does not derive from bone matrix degradation but is readily available in the bone marrow environment and, therefore, not necessarily dependent on osteoclast activity. Indeed, our previous studies have shown that isolated cancer cells and small foci detected shortly after their initial colonization of the bone are either independent of or much less reliant on spatial interactions with osteoclasts than are larger, more advanced lesions (17). Thus, it seems plausible that other compounds used in combination with bisphosphonates, such as those that target survival and/or proliferative pathways in cancer cells, may result in pronounced curative effects.…”

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confidence: 99%

“…The α receptor for platelet-derived growth factor (PDGFRα) is a receptor tyrosine kinase that has been correlated with advanced prostate carcinoma and was found associated with skeletal metastases by others (18)(19)(20) and us (17,21). The activation of this receptor in prostate cancer cells is responsible for the recruitment of the PI3K/Akt cell survival pathway.…”

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Targeting the α Receptor for Platelet-Derived Growth Factor as a Primary or Combination Therapy in a Preclinical Model of Prostate Cancer Skeletal Metastasis

Russell

Liu

Fatatis

2010

Clinical Cancer Research

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Purpose: Platelet-derived growth factor α (PDGFRα) is highly expressed in primary prostate cancer and associated skeletal metastases. Here, we tested whether targeting this receptor could impair metastatic colonization and progression, as well as prolong survival, either as primary or as combination therapy.Experimental Design: We used a preclinical animal model of metastasis in which PC3-ML human prostate cancer cells are inoculated directly in the blood circulation. First, the humanized, monoclonal antibody IMC-3G3 was administered to mice bearing established skeletal metastases. Second, we targeted the stromal PDGFRα with IMC-1E10, an antibody specific for the murine receptor. Third, IMC-3G3 and the bisphosphonate zoledronic acid (ZA), administered separately or in combination, were tested on the progression of skeletal lesions and overall survival. In addition, the ability of IMC-3G3 and ZA to impair initial colonization of the bone marrow by prostate cancer cells was investigated.Results: The blockade of PDGFRα on prostate cancer cells by IMC-3G3 reduces the size of established skeletal metastases, whereas the IMC-1E10 antibody directed against the stromal PDGFRα fails to inhibit metastatic progression. IMC-3G3 and ZA, either separately or in combination, significantly slow tumor growth and seem to prolong survival. Lastly, the blockade of PDGFRα by IMC-3G3 inhibits the initial phase of bone colonization, whereas ZA is ineffective at this stage.Conclusion: This study presents compelling evidence that targeting PDGFRα with IMC-3G3 delays the progression of early metastatic foci and reduces the size of more established lesions. In addition, IMC-3G3, either alone or in combination with ZA, prolongs survival in animal models. Although skeletal metastases occur with a significantly high rate in patients affected by advanced prostate carcinoma (1, 2), a limited range of options is currently available for the treatment of metastatic bone lesions (3, 4). Equally frustrating is the evidence that the burden deriving from skeletal dissemination represents the main cause of death for these patients, but the current standard of care for advanced prostate cancer produces merely palliative effects (5). Skeletal metastases cause bone resorption and chronic pain and predispose patients to skeletal-related events such as pathologic fractures and spinal cord compression. This skeletal morbidity is presently treated with the administration of bisphosphonates in prophylactic and adjuvant settings (6). Bisphosphonates are inorganic pyrophosphates that inhibit the enzymatic activities of osteoclasts, the cells responsible for the degradation of bone matrix (7,8). These compounds are effective in alleviating bone loss and pain, as well as reducing the occurrence of skeletal-related events (9, 10). However, bisphosphonates are not without side effects, including renal toxicity, hypocalcemia, and osteonecrosis of the jaw, which may prevent their long-term administration in bone-metastatic prostate cancer patients (11,12).In ...

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