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Tumor Biology |
Department of Adult Oncology [T. K., G. M., P. C. M., R. E. T., B. R., M. S., B. E. J., R. S.], and Department of Immunobiology [E. V. T.], Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115, and Division of Hematology and Oncology, Tufts-New England Medical Center, Boston, Massachusetts 02111 [P. C. M.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(SDF-1), was found to be the major chemokine receptor commonly expressed in all of the 10 SCLC cell lines tested. SCF and SDF-1 increased cellular proliferation over a course of 72 h in both the c-Kit- and the CXCR4-positive NCI-H69 SCLC cell line. Recently, SDF-1 and CXCR4 have been shown to be important regulators of migration and metastasis in breast and ovarian cancer. We found that SDF-1 dramatically increased cell motility and adhesion in CXCR4-expressing NCI-H446 SCLC cells. In addition, SDF-1 altered cell morphology with increased formation of filopodia and neurite-like projections. In NCI-H69 SCLC cells, SCF and SDF-1 cooperatively induced morphological changes and activated downstream signaling pathways. Treatment of NCI-H69 cells with STI571 specifically inhibited the c-Kit signaling events of Akt and p70 S6 kinase, whereas SDF-1-mediated activation of Akt or p70 S6 kinase was normal. In contrast, the phosphatidylinositol 3-kinase inhibitor, LY294002, prevented these cells from adhering and completely blocked SCF- and/or SDF-1-induced Akt or p70 S6 kinase phosphorylation. These results demonstrate that the CXCR4 receptor is functionally expressed in SCLC cells and may, therefore, be involved in the pathogenesis of SCLC in vivo. Inhibition of both the CXCR4 and the c-Kit downstream events could be a promising therapeutic approach in SCLC. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Chemokines are small cytokine-like peptides that direct various subsets of hematopoietic cells to home-specific anatomical sites through interaction with their G protein-coupled receptors (22
, 23) . CXCR4 is a seven-transmembrane G protein-coupled receptor and is also known as a coreceptor for HIV (24, 25, 26)
. SDF-1, the natural ligand for CXCR4, is a member of the CXC chemokine family that has chemotactic activity for hematopoietic progenitor cells (24
, 27, 28, 29)
. In hematopoietic cells, it has been shown that c-Kit and CXCR4 interact to provide homing to the bone marrow. SCF and SDF-1 can cooperatively enhance migration and proliferation potency in hematopoietic CD34+ progenitor cells (18, 19, 20, 21)
. Recently, CXCR4 has been shown to play an important role in migration and metastasis of solid tumors such as breast, ovarian cancers (30
, 31)
. Thus far, the role of interaction between chemokine receptors and cytokine receptors has not been defined for solid tumors such as SCLC.
In this report, we show that CXCR4 is the major chemokine receptor in SCLC and that SDF-1 can increase proliferation, cell adhesion, motility and change morphology and also cooperate with SCF to induce the downstream signaling targets Akt and p70 S6 kinase. By using the novel tyrosine kinase inhibitor STI571, c-Kit signaling events were inhibited, whereas SDF-1-mediated activation of Akt or p70 S6 kinase was normal in the treated cells. In contrast, the PI3-K inhibitor, LY294002, prevented these cells from adhering and completely blocked SCF- and/or SDF-1-induced Akt or p70 S6 kinase phosphorylation. It is known that stromal cells in the bone marrow and the lymph node produce considerable amounts of SCF and SDF-1, and, with the expression of c-Kit and CXCR4 in SCLC, this could be a potential mechanism of metastasis.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and SCF (BioSource International, Inc., Camarillo, CA) were used in the condition as indicated below.
Cell Viability Assay.
NCI-H69 cells (1 x 106/ml) were cultured in serum free (0.5% BSA) or serum containing (0.5, 1, 5, and 10% FCS) media with or without 100 ng/ml SCF and/or SDF-1. Viable cells were counted by trypan blue dye exclusion. Student’s t test was used for the statistical analysis and differences were considered statistically significant at P < 0.05.
RPA.
The specific mRNA for chemokine receptors was detected using the hCR-6 multiprobe template set (RiboQuant; PharMingen, San Diego, CA) according to the manufacturer’s protocol. This set contains DNA templates for CXCR-1, -2, -3, and -4; BLR-1/CXCR5; BLR-2/CCR7; and V28/CX3CR1; as well as ribosomal protein L32 and GAPDH as controls. RNase-protected probes were resolved on a denaturing 5% acrylamide-urea sequencing gel and identified by autoradiography.
Fluorescence-activated Cell Sorting Analysis.
Cells (1 x 105) were washed three times in PBS containing 0.5% BSA (PBS buffer), then incubated for 30 min at 4 °C with 10 µg/ml phycoerythrin-conjugated mouse-antihuman CXCR4 monoclonal antibody or phycoerythrin-labeled mouse control IgG2B (R&D Systems Inc., Minneapolis, MN). After washing the cells twice with PBS buffer to remove unbound antibodies, the stained cells were resuspended in 300 µl of PBS and analyzed by FACScan using Cell Quest software (Becton Dickinson Labware, Franklin Lakes, NJ).
Adhesion Assay.
The wells of a 96-well tissue culture plate (Corning-Costar, Cambridge, MA), precoated with 10 µg/ml human plasma FN or human col. IV (Life Technologies, Inc., Rockville, MD) overnight at 4°C, were washed with PBS twice and blocked for 1 h at 37°C with RPMI 1640 containing 0.2% BSA (adhesion media) before plating cells. NCI-H446 cells (3 x 105) were washed twice, resuspended in the adhesion media with or without SDF-1 (100 ng/ml), and plated onto uncoated, FN-coated, or col. IV-coated wells. Unattached cells were removed after incubation for 2 h at 37°C by gentle washing with adhesion media. The relative number of attached viable cells was determined by the MTT colorimetric assay (Sigma) following the instruction manual. Student’s t test was used for the statistical analysis of the attached cell number, and differences were considered significant at P < 0.05.
Analysis of Cell Motility by TLVM.
NCI-H446 cells were plated on cell culture dishes and placed into a temperature-controlled chamber at 37°C in an atmosphere of 5% CO2. The cells were examined by TLVM using an Olympus IX70 inverted microscope, Omega temperature controlled device, DVC1310 digital video camera, and QED Camera with Standalone 145 software. SDF-1 (100 ng/ml) was added into the culture after 6 h and images were recorded for another 10 h. Digital video images were saved every 90 s, and cell movement or morphological changes were analyzed with the NIH Image Analysis program. For movement analysis, the position of cell centroid was measured every 15 min and plotted to show the trace of centroid movement. The distance that the cell centroid traversed for each 90 s was calculated to determine the speed of the movement. For morphology analysis, the cell surface area and perimeter were measured to represent the degree of rugged shape. The frequency and period of formation and retraction of filopodia and uropods were also analyzed.
Immunoblotting.
Cells were lysed in lysis buffer [20 mM Tris (pH 8.0), 150 mM NaCl, 10% glycerol, 1% NP40, and 0.42% NaF] containing inhibitors (1 mM phenylmethylsulfonyl fluoride, 1 mM Na3VO4, 5 µg/ml aprotinin, and 5 µg/ml leupeptin). Cell lysates were separated by 7.5% SDS-PAGE under reducing conditions and transferred to nitrocellulose membranes (Schleicher and Schuell, Dassel, Germany). Proteins were detected by immunoblotting using an enhanced chemiluminescence technique (NEN Life Science Products, Boston, MA). Rabbit polyclonal antibodies against c-Kit (C-19; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), Akt, Akt (pSer 473), Akt (pThr 308), p70 S6 kinase, and p70 S6 kinase (pThr 389; Cell Signaling Technology, Inc., Beverly, MA) and monoclonal antibodies against ß-actin (AC-15; Sigma, St. Louis, MO) and phosphotyrosine (4G10; UBI, Lake Placid, NY) were used.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Expression of CXCR4 protein was confirmed by flow cytometric analysis in these SCLC cell lines and MO7e. The expression of CXCR4 was highest in NCI-H209 and NCI-H446 cells (Fig. 1B)
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SCF and SDF-1 Induce Proliferation of NCI-H69 Cells.
The effect of SCF and SDF-1 on viability in NCI-H69 cells was analyzed. As shown in Fig. 1
, NCI-H69 cells express both c-Kit and CXCR4, and, thus, these cells were used for many of the experiments. Without serum, neither SCF nor SDF-1 showed any effect on cell survival. On the other hand, in media containing 10% FCS, cell proliferation was significantly induced by SCF (21.5%; P = 0.0373) and SDF-1 (26.6%; P = 0.0133) separately, or in combination (26.6%; P = 0.0133), at 48 h compared with untreated control. SCF and SDF-1 conferred an increase in viable cell number at 72 h also (16.5%; P = 0.0164 and 15.5%; P = 0.0184, respectively, and 20.0%, P = 0.0322, combined). Even though SCF and SDF-1 individually induced proliferation of NCI-H69 cells, there was no additive or synergistic effect seen with both the cytokine and the chemokine combined (Fig. 2)
. Similar results were observed for different concentrations of FCS tested (0.5, 1, and 5% FCS; data not shown), implicating the importance of SCF and SDF-1 in the proliferation of NCI-H69 SCLC cells.
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Regulates Adhesion, Motility, and Cell Shape in NCI-H446 SCLC Cells. on cell motility and adhesion, NCI-H446 cells were used that express high amounts of CXCR4 and grow in an anchorage-dependent fashion. In an adhesion assay, FN (3.84-fold; P = 0.0002) and col. IV (2.98-fold; P = 0.0124) were found to increase the adhesion of NCI-H446 cells compared with the uncoated surface (Fig. 3)
. In conjunction with this, SDF-1 stimulation further increased the attachment 3.14-fold on the uncoated surface (P < 0.0001) but did not significantly enhance FN- and col. IV-mediated adhesion.
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also markedly increased the motility of NCI-H446 cells (Fig. 4, A and B)
with higher speed (Fig. 4C)
. Morphological changes from round to polygonal shape, including the formation of neurite-like projections, increased membrane ruffling, and more frequent filopodia and uropods formations, were observed in response to SDF-1 (Fig. 4)
. Filopodia formation in the presence of SDF-1 occurred much more frequently (13.14 versus 2.86 times/h/cell) with a longer existing period (6.09 versus 3.75 min/filopodium). Uropods formation was observed in four of seven (57.1%) of the SDF-1 treated cells; however, only one cell of seven (14.3%) untreated cells showed uropods. The lasting period per uropod also became much longer by SDF-1 stimulation (12.2 versus 5.0 min/uropod).
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-induced Cell Motility of NCI-H446 SCLC Cells.-induced cell motility in NCI-H446 SCLC cells. NCI-H446 cells either were left untreated or were treated with SDF-1 (100 ng/ml) in the absence or presence of LY294002 (25 µM). Phase-contrast pictures were taken at the 24-h time point. Most of the untreated cells kept their rounded shape and formed clusters, and nearly one-half of them attached weakly to the bottom of the dish (Fig. 5a)
. With SDF-1, almost all of the cells tightly adhered to the bottom of the dish, and neurite-like projections were induced in many cells (Fig. 5b)
. In the presence of LY294002, more than 90% of the cells were floating with rounded shape despite SDF-1 treatment, although they could form clumps (Fig. 5, c and d)
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(100 ng/ml) and/or SCF (100 ng/ml), in the absence or presence of STI571 (5 µM). Then, phase-contrast pictures were taken after 8 h (Fig. 6)
. Morphological changes began to be apparent from 4 h, and the changes plateaued after 8 h up to 24 h (data not shown). Neurite-like actin formations were observed in response to SCF (Fig. 6c)
, and this morphological change was more apparent as projections when treated with SDF-1 (Fig. 6, e and g)
. Neurite-like projections, induced by SDF-1 alone, still formed even in the presence of STI571 (Fig. 6f)
. Interestingly, STI571-treated NCI-H69 cells that were stimulated with both SDF-1 and SCF could not form any neurite-like structure (Fig. 6h)
. STI571 inhibited the morphological changes only in the presence of SCF (Fig. 6, b, d, and h)
. These results suggest that there are important interactions between CXCR4 and c-Kit in SCLC in terms of cell motility (34)
. The inhibition of the active c-Kit receptor by STI571 may lead to the inhibition of other active receptors such as CXCR4.
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and SCF Independently Regulate Phosphorylation of Akt and p70 S6 Kinase. and SCF signaling (4
, 35, 36, 37, 38)
. The activity of the PI3-K downstream targets Akt and p70 S6 kinase is regulated through critical serine/threonine (Ser/Thr) residues (39
, 40)
. Both, SDF-1 (Fig. 7A)
and SCF (Fig. 7B)
, induced time-dependent tyrosine phosphorylation of cellular proteins and Ser/Thr phosphorylation of Akt and p70 S6 kinase in NCI-H69 cells. Several tyrosine-phosphorylated bands between Mr 70,000 and Mr 120,000 were identified within 15 min of SDF-1 (50 ng/ml) stimulation. On the other hand, maximal tyrosine phosphorylation of proteins at Mr 60,000–90,000 and 110,000–145,000 occurred within 2.5–7.5 min in response to SCF (50 ng/ml). We also performed dose-response studies and found that optimal phosphorylation of cellular proteins was obtained with at least 25 ng/ml SDF-1 and 10 ng/ml SCF (data not shown). Phosphorylation of Akt (Ser 473) and p70 S6 kinase (Thr 389) occurred in response to SDF-1 within 5 min and in response to SCF within 2.5 min.
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and SCF in NCI-H69 cells. Cells were left untreated or were pretreated with STI571 (5 µM) or LY294002 (25 µM) overnight in serum-starved media and subsequently stimulated with 50 ng/ml SCF and/or SDF-1 for 15 min. Cooperative phosphorylation of Akt at Ser 473/Thr 308 and p70 S6 kinase at Thr 389 was induced by SCF and SDF-1 (Fig. 8)
. STI571 pretreatment inhibited SCF- but not SDF-1-induced phosphorylation. Expressions of Akt, p70 S6 kinase, and c-Kit were not affected by any of these treatments (Fig. 8A)
. In contrast, LY294002 pretreatment blocked SDF-1- as well as SCF-induced phosphorylation of Akt and p70 S6 kinase (Fig. 8B)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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stimulation in NCI-H69 cells with FCS in the media; whereas, when the survival of NCI-H69 cells was determined with SCF and SDF-1 without FCS, there was no significant antiapoptotic advantage observed. This would imply that both SCF and SDF-1 in these cells are important for cell growth. Interestingly, it has been shown that in the murine myeloid interleukin 3-dependent hematopoietic 32D cell line, SDF-1 has an inhibitory role in growth (41)
.
Chemokine receptors and cytokine receptors are crucial in the homing mechanisms of hematopoietic cells and the metastasis of solid tumors such as breast cancer and ovarian cancer. The initial step toward metastasis is increased cell motility and migration of cancer cells. Our results show that the SDF-1 stimulation of NCI-H446 cells leads to increased adhesion to uncoated surface and increased cell motility. At this time, we do not know the relevance of this in vivo. The enhancement of cell motility by SDF-1 is characterized by the increased formation of filopodia, uropods, and neurite-like projections as well as increased migratory movements. This change in morphology and motility in NCI-H446 cells is in contrast to Ba/F3 cells (interleukin 3-dependent pre-B cells expressing CXCR4) stimulated with SDF-1. The Ba/F3 cells do have increased cellular migration and increased membrane ruffling but have less dramatic change in morphology in response to SDF-1 (33)
. This may reflect the probability that hematopoietic cells have a different response to chemokines as compared with their response to solid tumors such as SCLC.
The functional expression of chemokine receptors has recently been described in several other solid tumors. CXCR4 and CCR7 are highly expressed in breast cancer and melanoma cells. In breast cancer cells, their respective ligands, SDF-1 and CCL21, mediated actin polimerization and pseudopodia formation and, subsequently, induced chemotactic and invasive responses in vitro. The neutralization of CXCR4 by a neutralizing antibody impaired the experimental metastasis of breast cancer cells to regional lymph nodes and to the lung in vivo (30)
. Robledo et al. (42)
have most recently shown that CXCR3 and CXCR4 are expressed in melanoma cells. The chemokine Mig, a ligand for CXCR3, activated the small GTPases RhoA and Rac1 and induced a reorganization of the actin cytoskeleton and cell migration. Both Mig and SDF-1 triggered modulation of integrin VLA-4 (4ß1)- and VLA-5 (5ß1)-dependent cell adhesion to FN. Scotton et al. (31)
have also reported that CXCR4 was expressed in 4 of 6 ovarian cancer cell lines and 8 of 10 primary ovarian tumors. AMD3100, a CXCR4 antagonist that is currently under clinical trial for HIV/AIDS, would be a potential therapeutic molecule to use in SCLC (43)
.
c-Kit is expressed in 
40–70% of SCLCs and is functionally stimulated by its ligand SCF (6, 7, 8, 9, 10, 11)
. Using transwell migration assays, SCF has been shown to act as a chemotactic signal (9)
. Through in vitro modeling, it has been hypothesized that SCF, in synergy with SDF-1, can mobilize hematopoietic CD34+ stem cells from the bone marrow to peripheral organs such as the spleen (18, 19, 20)
. We show that, in using NCI-H69 SCLC cells, SCF and SDF-1 can act cooperatively to enhance not only cell motility but also signal transduction by phosphorylating Akt and p70 S6 kinase. Both SCF and SDF-1 signal through PI3-K-dependent pathways that converge in the activation of the Ser/Thr kinases Akt and p70 S6 kinase. Phosphorylation of Akt on Thr 308 and Ser 473 or of p70 S6 kinase on Thr 229 correlates with their activation and occurs through direct phosphorylation by the phosphoinositide-dependent kinase-1 (PDK-1; Refs. 40
and 44
). p70 S6 kinase regulates cell cycle progression through phosphorylation of the S6 protein of the 40S ribosomal subunit (40)
. Akt controls the activation of several downstream molecules that regulate cell survival and apoptosis, including Forkhead transcription factors, Caspase 9, or Bad (45, 46, 47)
. This suggests that, in addition to activated tyrosine kinase receptors, CXCR4 in SCLC cells may well play an important role in tumor progression.
We have used small-molecule inhibitors to dissect out the pathways related to the downstream signaling events of c-Kit and CXCR4. c-Kit activity is inhibited by STI571 in SCLC and in gastrointestinal stromal tumors (14, 15, 16
, 48)
. Through using STI571, we have shown that the cell motility of NCI-H69 cells was abrogated in SCF/SDF-1-treated cells. This would imply that c-Kit/CXCR4 pathways cooperate to induce cell motility; however, the signal transduction pathway in SCF/SDF-1 treated cells was abolished only in the c-Kit pathway with STI571 treatment. Thus, the changes in morphology and motility in relation to biochemical changes in the phosphorylation of Akt and p70 S6 kinase are probably two separate events.
Also from our data, when c-Kit pathway is inhibited by STI571, the CXCR4 signal transduction pathway is still functional. However, when the PI3-K pathway is inhibited with LY294002, the c-Kit and CXCR4 signal transduction pathways are both inhibited. This would implicate PI3-K as an important intermediate messenger molecule in the signal transduction of c-Kit and CXCR4. PI3-K is also important in cell motility and alteration in cell morphology because LY294002 abrogated SDF-1-induced cytoskeletal phenomena in SCLC cells. Interestingly, SDF1-induced proliferation in H69 cells can also be inhibited by STI571 (data not shown). This may be caused by a STI571-sensitive autocrine mechanism (involving SCF-induced cell proliferation and survival) that is likely to be insufficient to induce cell migration and motility.
In summary, our data show that CXCR4 is expressed in all of the SCLC cell lines tested and cooperates with c-Kit in terms of biological and biochemical functions. The two receptors cooperate to enhance cell motility and migration, as well as to induce phosphorylation of viability-signaling molecules such as Akt and p70 S6 kinase. It would be useful to determine the effects of small-molecule drugs in the context of c-Kit or CXCR4, and STI571 is already being used in clinical trials.
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Department of Adult Oncology, Dana 1234B, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-4389; Fax: (617) 632-4379; E-mail: ravi_salgia{at}dfci.harvard.edu 
2 The abbreviations used are: SCLC, small cell lung cancer; RTK, receptor tyrosine kinase; SCF, stem cell factor; SDF, stromal cell-derived factor; PI3-K, phosphatidylinositol 3-kinase; RPA, RNase protection assay; BLR, Burkitt’s lymphoma receptor; GAPDH, glyceradehyde-3-phosphate dehydrogenase; FN, fibronectin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TLVM, time-lapse video microscopy; col. IV, collagen type IV.
Received 6/ 7/02. Accepted 9/ 4/02.
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 J. T. Kaifi, E. F. Yekebas, P. Schurr, D. Obonyo, R. Wachowiak, P. Busch, A. Heinecke, K. Pantel, and J. R. Izbicki Tumor-Cell Homing to Lymph Nodes and Bone Marrow and CXCR4 Expression in Esophageal Cancer J Natl Cancer Inst, December 21, 2005; 97(24): 1840 - 1847. [Abstract] [Full Text] [PDF]
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J. Tsurutani, K. A. West, J. Sayyah, J. J. Gills, and P. A. Dennis Inhibition of the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway but not the MEK/ERK Pathway Attenuates Laminin-Mediated Small Cell Lung Cancer Cellular Survival and Resistance to Imatinib Mesylate or Chemotherapy Cancer Res., September 15, 2005; 65(18): 8423 - 8432. [Abstract] [Full Text] [PDF]
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A. Katayama, T. Ogino, N. Bandoh, S. Nonaka, and Y. Harabuchi Expression of CXCR4 and Its Down-Regulation by IFN-{gamma} in Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., April 15, 2005; 11(8): 2937 - 2946. [Abstract] [Full Text] [PDF]
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T. Ara, K. Tokoyoda, R. Okamoto, P. A. Koni, and T. Nagasawa The role of CXCL12 in the organ-specific process of artery formation Blood, April 15, 2005; 105(8): 3155 - 3161. [Abstract] [Full Text] [PDF]
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S.-B. Peng, V. Peek, Y. Zhai, D. C. Paul, Q. Lou, X. Xia, T. Eessalu, W. Kohn, and S. Tang Akt Activation, but not Extracellular Signal-Regulated Kinase Activation, Is Required for SDF-1{alpha}/CXCR4-Mediated Migration of Epitheloid Carcinoma Cells Mol. Cancer Res., April 1, 2005; 3(4): 227 - 236. [Abstract] [Full Text] [PDF]
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C. Recher, O. Beyne-Rauzy, C. Demur, G. Chicanne, C. Dos Santos, V. M.-D. Mas, D. Benzaquen, G. Laurent, F. Huguet, and B. Payrastre Antileukemic activity of rapamycin in acute myeloid leukemia Blood, March 15, 2005; 105(6): 2527 - 2534. [Abstract] [Full Text] [PDF]
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S. Scala, A. Ottaiano, P. A. Ascierto, M. Cavalli, E. Simeone, P. Giuliano, M. Napolitano, R. Franco, G. Botti, and G. Castello Expression of CXCR4 Predicts Poor Prognosis in Patients with Malignant Melanoma Clin. Cancer Res., March 1, 2005; 11(5): 1835 - 1841. [Abstract] [Full Text] [PDF]
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F. Marchesi, P. Monti, B. E. Leone, A. Zerbi, A. Vecchi, L. Piemonti, A. Mantovani, and P. Allavena Increased Survival, Proliferation, and Migration in Metastatic Human Pancreatic Tumor Cells Expressing Functional CXCR4 Cancer Res., November 15, 2004; 64(22): 8420 - 8427. [Abstract] [Full Text] [PDF]
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G. G. Vaday, S.-B. Hua, D. M. Peehl, M. H. Pauling, Y.-H. Lin, L. Zhu, D. M. Lawrence, H. D. Foda, and S. Zucker CXCR4 and CXCL12 (SDF-1) in Prostate Cancer: Inhibitory Effects of Human Single Chain Fv Antibodies Clin. Cancer Res., August 15, 2004; 10(16): 5630 - 5639. [Abstract] [Full Text] [PDF]
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N. C. Wolff, D. E. Randle, M. J. Egorin, J. D. Minna, and R. L. Ilaria Jr. Imatinib Mesylate Efficiently Achieves Therapeutic Intratumor Concentrations in Vivo but Has Limited Activity in a Xenograft Model of Small Cell Lung Cancer Clin. Cancer Res., May 15, 2004; 10(10): 3528 - 3534. [Abstract] [Full Text] [PDF]
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 K.-i. Oonakahara, W. Matsuyama, I. Higashimoto, M. Kawabata, K. Arimura, and M. Osame Stromal-Derived Factor-1{alpha}/CXCL12-CXCR 4 Axis Is Involved in the Dissemination of NSCLC Cells into Pleural Space Am. J. Respir. Cell Mol. Biol., May 1, 2004; 30(5): 671 - 677. [Abstract] [Full Text] [PDF]
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 J. Matsui, T. Wakabayashi, M. Asada, K. Yoshimatsu, and M. Okada Stem Cell Factor/c-kit Signaling Promotes the Survival, Migration, and Capillary Tube Formation of Human Umbilical Vein Endothelial Cells J. Biol. Chem., April 30, 2004; 279(18): 18600 - 18607. [Abstract] [Full Text] [PDF]
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 J.-P. Spano, F. Andre, L. Morat, L. Sabatier, B. Besse, C. Combadiere, P. Deterre, A. Martin, J. Azorin, D. Valeyre, et al. Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome Ann. Onc., April 1, 2004; 15(4): 613 - 617. [Abstract] [Full Text] [PDF]
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R. A. Bartolome, B. G. Galvez, N. Longo, F. Baleux, G. N. P. van Muijen, P. Sanchez-Mateos, A. G. Arroyo, and J. Teixido Stromal Cell-Derived Factor-1{alpha} Promotes Melanoma Cell Invasion across Basement Membranes Involving Stimulation of Membrane-Type 1 Matrix Metalloproteinase and Rho GTPase Activities Cancer Res., April 1, 2004; 64(7): 2534 - 2543. [Abstract] [Full Text] [PDF]
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N. Sato, N. Fukushima, A. Maitra, C. A. Iacobuzio-Donahue, N. T. van Heek, J. L. Cameron, C. J. Yeo, R. H. Hruban, and M. Goggins Gene Expression Profiling Identifies Genes Associated with Invasive Intraductal Papillary Mucinous Neoplasms of the Pancreas Am. J. Pathol., March 1, 2004; 164(3): 903 - 914. [Abstract] [Full Text] [PDF]
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K. Jankowski, M. Kucia, M. Wysoczynski, R. Reca, D. Zhao, E. Trzyna, J. Trent, S. Peiper, M. Zembala, J. Ratajczak, et al. Both Hepatocyte Growth Factor (HGF) and Stromal-Derived Factor-1 Regulate the Metastatic Behavior of Human Rhabdomyosarcoma Cells, But Only HGF Enhances Their Resistance to Radiochemotherapy Cancer Res., November 15, 2003; 63(22): 7926 - 7935. [Abstract] [Full Text] [PDF]
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 J. B. Rubin, A. L. Kung, R. S. Klein, J. A. Chan, Y. Sun, K. Schmidt, M. W. Kieran, A. D. Luster, and R. A. Segal A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors PNAS, November 11, 2003; 100(23): 13513 - 13518. [Abstract] [Full Text] [PDF]
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K. Klarmann, M. Ortiz, M. Davies, and J. R. Keller Identification of in vitro growth conditions for c-Kit-negative hematopoietic stem cells Blood, November 1, 2003; 102(9): 3120 - 3128. [Abstract] [Full Text] [PDF]
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A. R. Cardones, T. Murakami, and S. T. Hwang CXCR4 Enhances Adhesion of B16 Tumor Cells to Endothelial Cells in Vitro and in Vivo via {beta}1 Integrin Cancer Res., October 15, 2003; 63(20): 6751 - 6757. [Abstract] [Full Text] [PDF]
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P. C. Ma, T. Kijima, G. Maulik, E. A. Fox, M. Sattler, J. D. Griffin, B. E. Johnson, and R. Salgia c-MET Mutational Analysis in Small Cell Lung Cancer: Novel Juxtamembrane Domain Mutations Regulating Cytoskeletal Functions Cancer Res., October 1, 2003; 63(19): 6272 - 6281. [Abstract] [Full Text] [PDF]
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T. Ishida, A. Utsunomiya, S. Iida, H. Inagaki, Y. Takatsuka, S. Kusumoto, G. Takeuchi, S. Shimizu, M. Ito, H. Komatsu, et al. Clinical Significance of CCR4 Expression in Adult T-Cell Leukemia/Lymphoma: Its Close Association with Skin Involvement and Unfavorable Outcome Clin. Cancer Res., September 1, 2003; 9(10): 3625 - 3634. [Abstract] [Full Text] [PDF]
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 C. R. Cogle, S. M. Guthrie, R. C. Sanders, W. L. Allen, E. W. Scott, and B. E. Petersen An Overview of Stem Cell Research and Regulatory Issues Mayo Clin. Proc., August 1, 2003; 78(8): 993 - 1003. [Abstract] [PDF]
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F. H. Blackhall, M. Pintilie, M. Michael, N. Leighl, R. Feld, M.-S. Tsao, and F. A. Shepherd Expression and Prognostic Significance of Kit, Protein Kinase B, and Mitogen-activated Protein Kinase in Patients with Small Cell Lung Cancer Clin. Cancer Res., June 1, 2003; 9(6): 2241 - 2247. [Abstract] [Full Text] [PDF]
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, 21.5%, P = 0.0373) and SDF-1
, 26.6%, P = 0.0133) separately or in combination (
, 26.6%, P = 0.0133) at 48 h compared with untreated control. SCF and SDF-1
, P < 0.05).
) or absence (
