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Suling Liu,
Christophe Ginestier,
Sing J Ou,
Shawn G Clouthier,
Shivani H Patel,
Florence Monville,
Hasan Korkaya,
Amber Heath,
Julie Dutcher,
Celina G Kleer,
Younghun Jung,
Gabriela Dontu, Russell Taichman,
Max S Wicha
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ABSTRACT: We have used in vitro and mouse xenograft models to examine the interaction between breast cancer stem cells (CSC) and bone marrow-derived mesenchymal stem cells (MSC). We show that both of these cell populations are organized in a cellular hierarchy in which primitive aldehyde dehydrogenase expressing mesenchymal cells regulate breast CSCs through cytokine loops involving IL6 and CXCL7. In NOD/SCID mice, labeled MSCs introduced into the tibia traffic to sites of growing breast tumor xenografts where they accelerated tumor growth by increasing the breast CSC population. With immunochemistry, we identified MSC-CSC niches in these tumor xenografts as well as in frozen sections from primary human breast cancers. Bone marrow-derived MSCs may accelerate human breast tumor growth by generating cytokine networks that regulate the CSC population.
Cancer Research 01/2011; 71(2):614-24. · 7.86 Impact Factor
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Russell S Taichman,
Zhuo Wang,
Yusuke Shiozawa,
Younghun Jung,
Junhui Song,
Alex Balduino,
Jincheng Wang,
Lalit R Patel,
Aaron M Havens,
Magdalena Kucia,
Mariusz Z Ratajczak,
Paul H Krebsbach
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ABSTRACT: A prospective in vivo assay was used to identify cells with potential for multiple lineage differentiation. With this assay, it was first determined that the 5-fluorouracil resistant cells capable of osseous tissue formation in vivo also migrated toward stromal derived factor-1 (SDF-1) in vitro. In parallel, an isolation method based on fluorescence-activated cell sorting was employed to identify a very small cell embryonic-like Lin-/Sca-1+CD45- cell that with as few as 500 cells was capable of forming bone-like structures in vivo. Differential marrow fractionation studies determined that the majority of the Lin-Sca-1+CD45- cells reside in the subendosteal regions of marrow. To determine whether these cells were capable of differentiating into multiple lineages, stromal cells harvested from Col2.3 Delta TK mice were implanted with a gelatin sponge into SCID mice to generate thymidine kinase sensitive ossicles. At 1.5 months, 2,000 green fluorescent protein (GFP)+ Lin-Sca-1+CD45- cells were injected into the ossicles. At harvest, colocalization of GFP-expressing cells with antibodies to the osteoblast-specific marker Runx-2 and the adipocyte marker PPAP gamma were observed. Based on the ability of the noncultured cells to differentiate into multiple mesenchymal lineages in vivo and the ability to generate osseous tissues at low density, we propose that this population fulfills many of the characteristics of mesenchymal stem cells.
Stem cells and development 05/2010; 19(10):1557-70. · 4.15 Impact Factor
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ABSTRACT: Stromal derived factor-1 (SDF-1 or CXCL12) expressed by osteoblasts and endothelial cells, and its receptors CXCR4 and CXCR7/RDC1 are key molecular determinants in prostate cancer (PCa) metastasis. What drives PCa cells into the extravascular marrow space(s) once they make contact with the blood vessel endothelium, however remains unclear. Here, we evaluated whether degradation of CXCL12 facilitates PCa cell entry into the marrow cavity by locally lowering CXCL12 levels intravascularly. To explore this possibility, co-cultured conditioned media from PCa cells and endothelial cells were evaluated for their ability to degrade biotinylated CXCL12 (bCXCL12). Co-culture of PCa cells/endothelial cells resulted in greater digestion of CXCL12 than was achieved by either cell type alone, and this activity regulated invasion in vitro. The ability to degrade CXCL12 was not however observed in PCa and osteoblasts co-cultures. Fractionation and inhibitor studies suggested that the activity was CD26/dipeptidyl peptidase IV (DPPIV) and possibly other cysteine/serine proteases. By inhibiting CD26/DPPIV, invasion and metastasis of PCa cell lines were enhanced in in vitro and in vivo metastasis assays. Together, these data suggest that the degradation of CXCL12 by CD26/DPPIV may be involved in the metastatic cascades of PCa, and suggests that inhibition of CD26/DPPIV may be a trigger of PCa metastasis.
Clinical and Experimental Metastasis 07/2008; 25(7):765-76. · 3.52 Impact Factor
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ABSTRACT: Bisphosphonates are useful for the treatment of prostate cancer bone metastasis. However, the role of bisphosphonate on the development of the osteoblastic component of prostate cancer bone metastases is not defined. In the present study, the third-generation bisphosphonate, YM529 (minodoronate), was tested for its effects on the osteolytic PC-3 and novel osteoblastic LNCaP-SF cell lines. YM529 inhibited both osteolytic and osteoblastic changes in an intratibial tumor injection murine model. In vitro, YM529 inhibited both the proliferation and the invasion of both prostate cancer cell lines. The stromal cell-derived factor-1 (or CXCL12)/CXCR-4 pathway is believed to play an important role in the development of prostate cancer bone metastases. Thus, we determined if YM529 affected this pathway. YM529 suppressed CXCR-4 expression in PC-3 and LNCaP-SF in vitro and in vivo and this was associated with decreased in vitro invasion. These results suggest that YM529 may inhibit cancer cell invasion into the bone matrix by repressing the expression of CXCR-4 in bone metastasis lesions.
Cancer Research 11/2005; 65(19):8818-25. · 7.86 Impact Factor
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ABSTRACT: Clusterin is an enigmatic glycoprotein that is overexpressed in several human cancers such as prostate and breast cancers, and squamous cell carcinoma. Because the suppression of clusterin expression renders human cancer cells sensitive to chemotherapeutic drug-mediated apoptosis, it is currently an antisense target in clinical trials for prostate cancer. However, the molecular mechanisms by which clusterin inhibits apoptosis in human cancer cells are unknown. Here we report that intracellular clusterin inhibits apoptosis by interfering with Bax activation in mitochondria. Intriguingly, in contrast to other inhibitors of Bax, clusterin specifically interacts with conformation-altered Bax in response to chemotherapeutic drugs. This interaction impedes Bax oligomerization, which leads to the release of cytochrome c from mitochondria and caspase activation. Moreover, we also find that clusterin inhibits oncogenic c-Myc-mediated apoptosis by interacting with conformation-altered Bax. Clusterin promotes c-Myc-mediated transformation in vitro and tumour progression in vivo. Taken together, our results suggest that the elevated level of clusterin in human cancers may promote oncogenic transformation and tumour progression by interfering with Bax pro-apoptotic activities.
Nature Cell Biology 10/2005; 7(9):909-15. · 19.49 Impact Factor
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ABSTRACT: Generalized lymphadenopathy is a rare presentation of prostate cancer. We report a case and review reported cases in the literature. Because of the association of chemokine receptor expression with specific metastatic patterns, we tested for expression of chemokine receptors known to mediate migration to lymph nodes.
We performed a MEDLINE (National Library of Medicine, Bethesda, MD) database search for case reports during the last 32 years using "prostate cancer," "lymphadenopathy," "metastatic to lymph nodes," and "mimicking lymphoma" as keywords. Expression of the CXCR4 and CCR7 chemokine receptors was assessed by immunohistochemistry. Laser capture microdissection and reverse transcription polymerase chain reaction for CXCR4 were used to exclude nonspecific binding.
Of 153 patients with prostate cancer presenting with lymphadenopathy (LAD) described in the literature, 67 (44%) presented with supraclavicular adenopathy, 29 (19%) retroperitoneal, 22 (14%) mediastinal, 15 (10%) cervical, 9 (6%) inguinal, and 2 (1%) axillary LAD. Only 9 patients presenting with generalized LAD have been previously reported. Monoclonal antibodies to CCR7 showed intense staining in the patient's tumor epithelium. Little or no staining was observed for CXCR4. Reverse transcription polymerase chain reaction for chemokine receptors on ribonucleic acid (RNA) recovered from the patient's sample failed to express messenger RNA for CXCR4 but did express messenger RNA for CCR1, CCR4, and CCR5.
Prostate cancer may present on rare occasions with generalized adenopathy. Variable expression of chemokine receptors may be associated with organ specific patterns of metastasis. In this case, expression of CCR7 may have accounted for the unusual predilection of this patient's prostate cancer for lymph nodes.
Urologic Oncology 23(4):261-7. · 3.22 Impact Factor
