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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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Brain metastasis mouse model: SapC-DOPS-targeting and anatomical and molecular features(A) Tumor cell luminescence (Luc) and SapC-DOPS-CVM fluorescence colocalize in vivo. SapC-DOPS-CVM was injected via the tail vein and the mouse imaged 24 hs later. B) H&E staining of a metastatic mouse brain. (C) Phosphatidylserine (PS) expression in a micrometastasis, as assessed by immunofluorescence in a mouse brain section. (D) Immunofluorescence against the mitosis marker Ki-67 (human) reveals active proliferation of MDA-MB-231-luc-D3H2LN cells in a mouse brain section. (E) Perivascular growth of breast cancer-derived MDA-MB-231-luc-D3H2LN cells in a mouse brain. Both capillary remodeling (arrowheads) and vessel co-option (arrows) characterize tumor cell growth. Scale bars = 25 μm (C); 200 μm (D, E).
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Figure 6: Brain metastasis mouse model: SapC-DOPS-targeting and anatomical and molecular features(A) Tumor cell luminescence (Luc) and SapC-DOPS-CVM fluorescence colocalize in vivo. SapC-DOPS-CVM was injected via the tail vein and the mouse imaged 24 hs later. B) H&E staining of a metastatic mouse brain. (C) Phosphatidylserine (PS) expression in a micrometastasis, as assessed by immunofluorescence in a mouse brain section. (D) Immunofluorescence against the mitosis marker Ki-67 (human) reveals active proliferation of MDA-MB-231-luc-D3H2LN cells in a mouse brain section. (E) Perivascular growth of breast cancer-derived MDA-MB-231-luc-D3H2LN cells in a mouse brain. Both capillary remodeling (arrowheads) and vessel co-option (arrows) characterize tumor cell growth. Scale bars = 25 μm (C); 200 μm (D, E).

Mentions: The ability of SapC-DOPS to target brain metastases was evaluated in two metastatic brain tumor models, generated by injecting human breast cancer cells (MDA-MB-231-luc-D3H2LN) or human lung cancer cells (NCI-H460) into the internal carotid artery of nude mice. Fig. 6A shows an example of the luciferase bioluminescent signal (Luc) detected 51 days after injection of MDA-MB-231-luc-D3H2LN cancer cells in a live mouse, indicating the presence of tumor cells in the brain. Overlapping SapC-DOPS-CVM fluorescence, registered after a single intravenous injection, was indicative of SapC-DOPS's specific targeting of tumor cells (Fig. 6A, right side). Brain histology in these mice revealed multifocal micro- and macrometastases of epithelial morphology located predominantly in the hippocampal region (Fig. 6B); in some cases, metastatic cells were also found in the cortex, basal ganglia, and cerebellum. These cells strongly expressed phosphatidylserine (Fig. 6C) and evidenced extensive mitosis, as shown by immunostaining against the proliferation marker Ki-67 (Fig. 6D). Vascular labeling with lectin-FITC showed that MDA-MB-231-luc-D3H2LN tumor cells grow both as compact clusters, surrounding capillary structures, and also along preexisting vessels (Fig. 6E).


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)

Brain metastasis mouse model: SapC-DOPS-targeting and anatomical and molecular features(A) Tumor cell luminescence (Luc) and SapC-DOPS-CVM fluorescence colocalize in vivo. SapC-DOPS-CVM was injected via the tail vein and the mouse imaged 24 hs later. B) H&E staining of a metastatic mouse brain. (C) Phosphatidylserine (PS) expression in a micrometastasis, as assessed by immunofluorescence in a mouse brain section. (D) Immunofluorescence against the mitosis marker Ki-67 (human) reveals active proliferation of MDA-MB-231-luc-D3H2LN cells in a mouse brain section. (E) Perivascular growth of breast cancer-derived MDA-MB-231-luc-D3H2LN cells in a mouse brain. Both capillary remodeling (arrowheads) and vessel co-option (arrows) characterize tumor cell growth. Scale bars = 25 μm (C); 200 μm (D, E).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Brain metastasis mouse model: SapC-DOPS-targeting and anatomical and molecular features(A) Tumor cell luminescence (Luc) and SapC-DOPS-CVM fluorescence colocalize in vivo. SapC-DOPS-CVM was injected via the tail vein and the mouse imaged 24 hs later. B) H&E staining of a metastatic mouse brain. (C) Phosphatidylserine (PS) expression in a micrometastasis, as assessed by immunofluorescence in a mouse brain section. (D) Immunofluorescence against the mitosis marker Ki-67 (human) reveals active proliferation of MDA-MB-231-luc-D3H2LN cells in a mouse brain section. (E) Perivascular growth of breast cancer-derived MDA-MB-231-luc-D3H2LN cells in a mouse brain. Both capillary remodeling (arrowheads) and vessel co-option (arrows) characterize tumor cell growth. Scale bars = 25 μm (C); 200 μm (D, E).
Mentions: The ability of SapC-DOPS to target brain metastases was evaluated in two metastatic brain tumor models, generated by injecting human breast cancer cells (MDA-MB-231-luc-D3H2LN) or human lung cancer cells (NCI-H460) into the internal carotid artery of nude mice. Fig. 6A shows an example of the luciferase bioluminescent signal (Luc) detected 51 days after injection of MDA-MB-231-luc-D3H2LN cancer cells in a live mouse, indicating the presence of tumor cells in the brain. Overlapping SapC-DOPS-CVM fluorescence, registered after a single intravenous injection, was indicative of SapC-DOPS's specific targeting of tumor cells (Fig. 6A, right side). Brain histology in these mice revealed multifocal micro- and macrometastases of epithelial morphology located predominantly in the hippocampal region (Fig. 6B); in some cases, metastatic cells were also found in the cortex, basal ganglia, and cerebellum. These cells strongly expressed phosphatidylserine (Fig. 6C) and evidenced extensive mitosis, as shown by immunostaining against the proliferation marker Ki-67 (Fig. 6D). Vascular labeling with lectin-FITC showed that MDA-MB-231-luc-D3H2LN tumor cells grow both as compact clusters, surrounding capillary structures, and also along preexisting vessels (Fig. 6E).

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