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Phosphatidylserine-selective targeting and anticancer effects of SapC-DOPS nanovesicles on brain tumors.

Blanco VM, Chu Z, Vallabhapurapu SD, Sulaiman MK, Kendler A, Rixe O, Warnick RE, Franco RS, Qi X - Oncotarget (2014)

Bottom Line: These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature.In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity.Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.

ABSTRACT
Brain tumors, either primary (e.g., glioblastoma multiforme) or secondary (metastatic), remain among the most intractable and fatal of all cancers. We have shown that nanovesicles consisting of Saposin C (SapC) and dioleylphosphatidylserine (DOPS) are able to effectively target and kill cancer cells both in vitro and in vivo. These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature. In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity. Second, we demonstrate that SapC-DOPS selectively targets brain metastases-forming cancer cells both in vitro, in co-cultures with human astrocytes, and in vivo, in mouse models of brain metastases derived from human breast or lung cancer cells. Third, we demonstrate that SapC-DOPS have cytotoxic activity against metastatic breast cancer cells in vitro, and prolong the survival of mice harboring brain metastases. Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

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Tumor-stromal markers of brain metastasis(A) Immunofluorescence against the astrocytic marker GFAP shows extensive glial reactivity in a hippocampus harboring brain micrometastases (arrows). The contralateral hippocampus shows normal GFAP staining pattern. (B) Mouse nestin immunolabeling reveals numerous nestin-positive host cells with glial or endothelial morphologies in a brain region colonized by metastatic cancer cells. (C) Double immunofluorescence staining against CD11b and VEGFR1 in a metastatic mouse brain. Note the extensive coverage of cancer cells by CD11b-positive microglia/macrophages, while VEGFR1 expression seems to be restricted to metastatic cells. Scale bars = 200 μm (A, B); 20 μm (B, inset); 50 μm (C).
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Figure 7: Tumor-stromal markers of brain metastasis(A) Immunofluorescence against the astrocytic marker GFAP shows extensive glial reactivity in a hippocampus harboring brain micrometastases (arrows). The contralateral hippocampus shows normal GFAP staining pattern. (B) Mouse nestin immunolabeling reveals numerous nestin-positive host cells with glial or endothelial morphologies in a brain region colonized by metastatic cancer cells. (C) Double immunofluorescence staining against CD11b and VEGFR1 in a metastatic mouse brain. Note the extensive coverage of cancer cells by CD11b-positive microglia/macrophages, while VEGFR1 expression seems to be restricted to metastatic cells. Scale bars = 200 μm (A, B); 20 μm (B, inset); 50 μm (C).

Mentions: To better characterize this brain metastasis model, we performed immunohistochemistry to define potential tumor-stromal interactions. Brain regions affected with metastases showed marked astrogliosis as evidenced by GFAP immunostaining (Fig. 7A). Nestin-expressing host cells with stellate morphology were also prominently observed in close proximity to tumor cells (Fig. 7B); nestin expression sometimes overlapped with vascular (lectin) stain (not shown), suggesting a possible role of nestin-positive host cells in tumor vasculogenesis. Tumor cells were also tightly surrounded by CD11b-expressing myeloid cells and stained positively for the VEGF receptor VEGFR1 (Fig. 7C).


Phosphatidylserine-selective targeting and anticancer effects of SapC-DOPS nanovesicles on brain tumors.

Blanco VM, Chu Z, Vallabhapurapu SD, Sulaiman MK, Kendler A, Rixe O, Warnick RE, Franco RS, Qi X - Oncotarget (2014)

Tumor-stromal markers of brain metastasis(A) Immunofluorescence against the astrocytic marker GFAP shows extensive glial reactivity in a hippocampus harboring brain micrometastases (arrows). The contralateral hippocampus shows normal GFAP staining pattern. (B) Mouse nestin immunolabeling reveals numerous nestin-positive host cells with glial or endothelial morphologies in a brain region colonized by metastatic cancer cells. (C) Double immunofluorescence staining against CD11b and VEGFR1 in a metastatic mouse brain. Note the extensive coverage of cancer cells by CD11b-positive microglia/macrophages, while VEGFR1 expression seems to be restricted to metastatic cells. Scale bars = 200 μm (A, B); 20 μm (B, inset); 50 μm (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196187&req=5

Figure 7: Tumor-stromal markers of brain metastasis(A) Immunofluorescence against the astrocytic marker GFAP shows extensive glial reactivity in a hippocampus harboring brain micrometastases (arrows). The contralateral hippocampus shows normal GFAP staining pattern. (B) Mouse nestin immunolabeling reveals numerous nestin-positive host cells with glial or endothelial morphologies in a brain region colonized by metastatic cancer cells. (C) Double immunofluorescence staining against CD11b and VEGFR1 in a metastatic mouse brain. Note the extensive coverage of cancer cells by CD11b-positive microglia/macrophages, while VEGFR1 expression seems to be restricted to metastatic cells. Scale bars = 200 μm (A, B); 20 μm (B, inset); 50 μm (C).
Mentions: To better characterize this brain metastasis model, we performed immunohistochemistry to define potential tumor-stromal interactions. Brain regions affected with metastases showed marked astrogliosis as evidenced by GFAP immunostaining (Fig. 7A). Nestin-expressing host cells with stellate morphology were also prominently observed in close proximity to tumor cells (Fig. 7B); nestin expression sometimes overlapped with vascular (lectin) stain (not shown), suggesting a possible role of nestin-positive host cells in tumor vasculogenesis. Tumor cells were also tightly surrounded by CD11b-expressing myeloid cells and stained positively for the VEGF receptor VEGFR1 (Fig. 7C).

Bottom Line: These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature.In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity.Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.

ABSTRACT
Brain tumors, either primary (e.g., glioblastoma multiforme) or secondary (metastatic), remain among the most intractable and fatal of all cancers. We have shown that nanovesicles consisting of Saposin C (SapC) and dioleylphosphatidylserine (DOPS) are able to effectively target and kill cancer cells both in vitro and in vivo. These actions are a consequence of the affinity of SapC-DOPS for phosphatidylserine, an acidic phospholipid abundantly present in the outer membrane of a variety of tumor cells and tumor-associated vasculature. In this study, we first characterize SapC-DOPS bioavailability and antitumor effects on human glioblastoma xenografts, and confirm SapC-DOPS specificity towards phosphatidylserine by showing that glioblastoma targeting is abrogated after in vivo exposure to lactadherin, which binds phosphatidylserine with high affinity. Second, we demonstrate that SapC-DOPS selectively targets brain metastases-forming cancer cells both in vitro, in co-cultures with human astrocytes, and in vivo, in mouse models of brain metastases derived from human breast or lung cancer cells. Third, we demonstrate that SapC-DOPS have cytotoxic activity against metastatic breast cancer cells in vitro, and prolong the survival of mice harboring brain metastases. Taken together, these results support the potential of SapC-DOPS for the diagnosis and therapy of primary and metastatic brain tumors.

Show MeSH
Related in: MedlinePlus