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Molecular Oncology, Markers, Clinical Correlates |
Departments of Surgery and Surgical Basic Science [T. K., R. H., Y. M., J. I., S. T., S. N., M. K., H. K., R. D., M. I.], Hematology and Oncology [T. H.], and Pharmaceutical Science [N. F.], Kyoto University, Kyoto 606-4897, Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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SDF-1 was initially cloned by Tashiro et al. (10) and later identified as a growth factor for B cell progenitors, a chemotactic factor for T cells and monocytes, and in B-cell lymphopoiesis and bone marrow myelopoiesis (11, 12, 13) . SDF-1 is a member of the CXC subfamily of chemokines, and its chemotactic effect is mediated by the chemokine receptor CXCR4 (12 , 14) . Most of the chemokine receptors interact with pleural ligands, and vice versa, but the SDF-1/CXCR4 receptor ligand system has been shown to involve a one-on-one interaction (15 , 16) . Furthermore, CXCR4 has been shown to function as a coreceptor for T lymphocytotrophic HIV-1 isolates (17) . Recent studies have demonstrated that endothelial cells express CXCR4 and are strongly chemoattracted by SDF-1 (18, 19, 20) . Tachibana et al. (15) reported that in the embryo of CXCR4 or SDF-1 knockout mice larger branches of the superior mesenteric artery were missing and that the resultant abnormal circulatory system led to gastrointestinal hemorrhage and intestinal obstruction. These findings suggest that SDF-1 and CXCR4 are involved in organ vascularization, as well as in the immune and hematopoietic system.
Recently, several studies have been conducted to detect the mRNA expression of CXCR4 and SDF-1 in solid tumors. The results are not uniform, and the relevance to cancer progression and tumor angiogenesis is not determined (21 , 22) . To clarify the role of the SDF-1/CXCR4 receptor ligand system in pancreatic cancer, we have investigated the expression of CXCR4 and SDF-1 with the aid of immunohistochemical analysis and RT-PCR in pancreatic cancer tissue and experimental chemotactic activity of SDF-1 in pancreatic cancer cells and vascular endothelial cells in vitro.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pancreatic Cancer Tissues.
Samples of 52 invasive ductal adenocarcinomas were obtained from
patients with primary pancreatic cancers who underwent resection
surgery at the Department of Surgery and Surgical Basic Science, Kyoto
University, between 1991 and 1996. Samples were fixed in 4%
paraformaldehyde or 10% formalin and embedded in paraffin, after which
4-µm sections were cut and placed on silane-coated slides for
immunohistochemical studies. Part of the specimens was stained with H&E
and microscopically examined to confirm the diagnosis. The
clinicopathological characteristics of the 52 patients with ductal
adenocarcinomas of the pancreas who were the subjects of this study are
summarized in Table 1
. There were 25
males and 27 females, with an age range of 41–79 years (median age,
63.1). Approximately 3-mm sections from each tumorous tissue and
dissected lymph node were examined histologically to confirm the
diagnosis and identify tumor extension, lymph node metastasis, liver
metastasis, and stage of Union International Contre Cancer; the
cancer was then staged accordingly.
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Immunohistochemical Analysis.
The paraffin sections were dewaxed and pretreated in 0.01 M
sodium citrate buffer (pH 6.0) for 20 min at 95°C to unmask tissue
antigen. These sections were then incubated with 1% hydrogen peroxide
in methanol for 15 min at room temperature to block endogenous
peroxidase and then with PBS containing 5% normal goat serum for 30
min at room temperature to block any nonspecific reaction.
Immunostaining was performed with anti-CXCR4 antibody (100 ng/ml) at
4°C overnight. The sections were incubated with goat antimouse IgG
biotinylated second antibodies (Dakopatts, Glostrup, Denmark) diluted
1:300 for 1 h at room temperature and thereafter incubated in
streptavidin-peroxidase complex for 30 min. The sections were then
developed with diaminobenzidine-tetra-hydrochloride (0.03%) as the
substrate for 3 min, counterstained with Mayers hematoxylin, and
mounted. The evaluation of CXCR4 expression was simultaneously
performed by two investigators (T. K. and Y. M.) without knowledge of
the patients’ clinicopathological features. We decided that the
specimen should be regarded as positive when the intensity of staining
was moderate or strong and negative when the intensity of staining was
negative or weak. Several serial specimens of samples that were CXCR4
immunopositive were stained with anti-CD34 antibody to identify
vascular endothelial cells. Furthermore, we exposed nonspecific mouse
IgG as the primary antibody to several tissue specimens of pancreatic
cancer to confirm the specificity of the results, and none of them
showed any immunoreaction.
Cell Lines and Culture Conditions.
Five human pancreatic cancer cell lines (CFPAC-1, BxPC-3, HPAC,
AsPC-1, and PANC-1) and a human fetal lung fibroblast cell line (MRC-9)
were purchased from the American Type Culture Collection. HUVECs were
from Kurabo Industries (Osaka, Japan). The cell lines were maintained
in the following media at 37°C in a humid atmosphere of 5%
CO2/95% air: CFPAC-1 cells in Iscove’s modified
Dulbecco’s medium with 10% FBS, BxPC-3 cells in RPMI 1640 with 10%
FBS, PANC-1 cells in DMEM, AsPC-1 cells in RPMI 1640 with 10% FBS,
HPAC cells in DMEM/F-12 with 10% FBS, and HUVECs in S200 medium. Each
medium contained 100 units/ml penicillin and 100 µg/ml streptomycin.
RT-PCR.
Total RNA extraction from homogenized pieces of fresh frozen
tissues of eight pancreatic cancer and cultured cells was performed
with Trizol (Life Technologies, Inc., Eggenstein, Germany), according
to the acid guanidium thiocyanate-phenol-chloroform method.
cDNA was synthesized with random priming from 1 µg of total RNA with the aid of a First-Strand cDNA Synthesis kit (Pharmacia Biotech, Uppsala, Sweden), according to the manufacturer’s instructions. For the PCR reaction, 2 µl of cDNA solution were mixed with 2 µl of a specific primer (20 pM each), 5 µl of 10x reaction buffer, 10 µl of 1 mM dNTP mix, 0.5 µl of Taq DNA polymerase, and 28.5 µl of double distilled water for a total volume of 50 µl. The PCR reaction was performed in a Perkin-Elmer thermalcycler (Norwalk, CT) with the primers used for the amplification of SDF-1 and CXCR4 and specified below (26 , 27) . The amplification consisted of denaturation at 94°C for 30 s, annealing at 56°C for 30 s, and extension at 72°C for 30 s (33 cycles). A total of 10 µl of PCR products were separated onto 2.5% w/v agarose gels and stained with ethidium bromide.
Sense primers:
CXCR4, 5'-AGCTGTTGGTGAAAAGGTGGTCTATG-3'; and
SDF-1, 5'-CCGCGCTCTGCCTCAGCGACGGGAAG-3'.
Antisense primers:
CXCR4, 5'-GCGCTTCTGGTGGCCCTTGGAGTGTG-3'; and
SDF-1, 5'-CTTGTTTAAAGCTTTCTCCAGGTACT-3'.
Migration Assay for Pancreatic Cancer Cells and HUVECs.
Cell migration assays were performed in triplicate by using 6.5-mm
diameter chambers with 8-µm pore filters (Transwell, 24-well cell
cultures; Costar, Boston, MA). Fifty microliters of fibronectin (100
µg/ml) were coated on the lower surfaces of filters. The filters were
subsequently dried with air blown into a clean ventilator. AsPC-1 and
CFPAC-1 cells and HUVECs were suspended at 2 x
105 cells/ml in serum-free media (RPMI 1640
containing 1% BSA), and then 200 µl of the cell suspension were
added to the upper chamber. For AsPC-1 cells and HUVECs, 100 ng/ml
SDF-1, 100 ng/ml SDF-1 plus 10 µg/ml IVR7, or 100 ng/ml SDF-1 plus 1
µM T22 dissolved in 600 µl of serum-free media was
placed in the lower well. For CFPAC-1 cells, subconfluent MRC-9 cells,
or subconfluent MRC-9 cells plus 1 µM T22 were placed in
the lower well. The chambers were then incubated for 12 h (AsPC-1
cells and HUVECs) or 8 h (CFPAC-1 cells) at 37°C in a humid
atmosphere of 5% CO2/95% air. After incubation,
the filters were fixed in 10% acetic acid/90% methanol and stained
with H&E. The upper surfaces of the filters were scraped twice with
cotton swabs to remove nonmigrating cells. The experiments were
conducted in triplicate wells, and the number of migrating cells in
five high-power fields per filter were counted microscopically at x400
magnification. Because the background migration without chemokines or
fibroblasts varied among experiments, data were normalized as the
migration index: the number of migrating cells in an experimental
group/the number of migrating cells in control groups without
chemokines or fibroblasts.
Statistical Analysis.
The distribution of categorical data between CXCR4 immunostaining in
pancreatic cancers and clinicopathological characteristics were
assessed by 
2
test. Results of migration
assays were assessed with Student’s t test. The level of
significance was defined as P < 0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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shows representative immunostainings of
cancerous and noncancerous regions in pancreatic cancer tissues.
Staining of the CXCR4 protein was identified in the cytoplasm and/or
cell membrane of cancer cells, but was not detected in the normal
acinar cells and ductal cells of noncancerous region in pancreatic
cancer tissue. Negative or weak staining for the CXCR4 protein was
observed in a majority of the infiltrating inflammatory cells in the
specimens. The immunopositive ratio of cancer cells in the pancreatic
cancer tissue specimens was 71.2% (37 of 52). Table 1
summarizes the
relationship between CXCR4 expression and clinicopathological features
of 52 pancreatic cancers. There was no significant
correlation between the expression of CXCR4 protein and the
clinicopathological variables examined (i.e., tumor
extension, lymph node metastasis, liver metastasis, and Union
International Contre Cancer stage). CXCR4 immunoreactivities were
observed in endothelial cells of relatively large vessels around the
tumorous lesions, but were scarcely found in the endothelial cells of
microvessels inside tumorous lesions (Fig. 2, A and B)
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. On
the other hand, SDF-1 mRNA expression was not detected in five
pancreatic cancer cell lines and HUVECs, but was identified in eight
pancreatic cancer tissue samples (Fig. 3b)
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. At a concentration of 100
g/ml SDF-1 induced an approximately quadruple chemotaxis of HUVECs. One
micromolar of T22 caused a 33% reduction of the chemotaxis of
HUVECs in the presence of containing 100 ng/ml SDF-1 (Fig. 4b)
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9-fold chemotaxis of CFPAC-1 when
compared with that of control. T22 significantly reduced the
chemoattractive effect of MRC-9, but did not completely block this
effect (Fig. 4c)
. RT-PCR generated SDF-1 mRNA expression in
MRC-9 cells under these conditions (data not shown). |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, we first used immunohistochemical methods to examine CXCR4 expression in pancreatic cancer tissues. Immunoreactive CXCR4 was found in the cytoplasm and/or cell membrane of pancreatic cancer cells. Although CXCR4 staining in pancreatic cancer tissue was heterogeneous and showed differences between specimens, it was found mainly in cancer cells: the immunopositive ratio for the pancreatic cancer tissue specimens was 71.2% (37 of 52). There was a tendency for the immunopositive ratio of CXCR4 in tumors with lymph node metastasis or liver metastasis to be higher than in tumors without these features, but no statistically significant correlation with clinicopathological features were found. Several studies have demonstrated either overexpression or reduced expression of CXCR4 and SDF-1 mRNA in solid tumors. Sehgal et al. (21 , 28) reported overexpression of CXCR4 mRNA in glioblastoma multiform tumor tissue and breast cancer tissue. They also found that CXCR4 expression and its ligand interaction were deeply involved in cell proliferation in glioblastoma cell lines (28) . They concluded that CXCR4 plays an important role of proliferation and tumorigenic properties of human glioblastoma tumors (21 , 28) . Barnard and his colleagues (29 , 30) showed the contrary results that CXCR4 mRNA expression was reduced in hepatocellular carcinoma tissue when compared with noncancerous tissue, but was not changed in colon, esophageal, and gastric cancer. They also found reduced mRNA expression of SDF-1 in these malignant tissues (22) . Thus, there is a diversity of views on the role of the SDF-1/CXCR4 receptor ligand system in malignant tissues. In the current study, SDF-1 mRNA expressions were detected in all pancreatic cancer tissues (eight of eight) but were not detected in pancreatic cancer cell lines (zero of five), whereas CXCR4 mRNA was detected in both pancreatic cancer tissues (eight of eight) and cancer cell lines (five of five). The results indicate that the paracrine mechanism may be involved in the SDF-1/CXCR4 receptor ligand system in pancreatic cancer.
We have demonstrated that CXCR4 mRNA expression was present in HUVEC endothelial cell lines and that the migratory capability of HUVECs was increased by SDF-1 stimulation. Several other studies have demonstrated similar results. In situ hybridization and immunocytochemistry revealed both transcript and protein expression in cultured endothelial cells, as well as in the endothelium of normal aorta. SDF-1 stimulated mobilization of intracellular calcium at a moderate level, confirming the expression of a functional receptor on the endothelial surface (20) . The mRNA expression level of CXCR4 in vascular endothelial cells is highest of several CC and CXC chemokine receptors, and SDF-1 induced pronounced chemotaxis of vascular endothelial cells, and this effect was stronger than that of other chemokines such as gIP10, IL-8, MIP-1a, MCP-1, eotaxin, and RANTES (18) . Such evidence suggests that the SDF-1/CXCR4 receptor ligand system may be involved in angiogenesis.
Recently it has been demonstrated that SDF-1 plays an important role in organ vascularization. In CXCR4 knockout mice, the formation of the small vascular network that surrounds the stomach was well preserved, but the large vessels were missing, which led to hemorrhage and intestinal obstruction, and the mice lacking CXCR4 died in utero. As expected, SDF-1 knockout mice showed a similar phenotype (15 , 16) . In our immunohistochemical study of CXCR4 and CD34, CXCR4 protein expression was detected in the endothelial cells of relatively large vessels around tumorous lesions. We did not find the direct evidence of CXCR4 expression in microvessels inside the tumor; however, these findings suggest that SDF-1 may be involved in tumor growth by way of modeling relative large vessels in pancreatic cancer tissues.
T22 is a small synthesized peptide consisting of 18 amino acid residues, which is an analogue of polyphemusin II isolated from the hemocyte debris of American horseshoe crabs (23) . T22 is a CXCR4 antagonist that inhibits Ca2+ mobilization induced by SDF-1 stimulation through CXCR4, and IVR7 monoclonal antibody blocks HIV entry into T cells, as well as T22 (24 , 25) . In the current study, we first demonstrated that T22 significantly antagonized SDF-1-stimulated migration of AsPC-1 pancreatic cancer cells and HUVEC endothelial cells. IVR7, which was used in the immunohistochemical study, also significantly blocked chemoattractive action of SDF-1 in AsPC-1 cells. It is well known that the interaction between cancer cells and stromal cells is deeply involved in tumor invasion and metastasis. We were able to demonstrate that MRC-9 fibroblast cells significantly increased the migratory capability of CFPAC-1 cells and that T22 significantly reduced this capability when they are cocultured. In vitro findings indicate that SDF-1 acts as a chemoattractive factor for pancreatic cancer cells and endothelial cells and is, at least in part, involved in the mechanism of cancer cell migration resulting from fibroblast coculture. The mode of action of chemokines depends heavily on the local environment. Secreted SDF-1 is through to act by creating a gradient for CXCR4-bearing cells. The secreted protein may be localized by binding to extracellular matrix. In this situation, in vitro migration assays may not predict in vivo function. In vitro findings, however, indicate that SDF-1 acts as a chemoattractive factor for pancreatic cancer cells and endothelial cells and is, at least in part, involved in the mechanism of cancer cell migration resulting from fibroblast coculture.
In conclusion, our results suggest that the SDF-1/CXCR4 receptor ligand system may have a possible role in the pancreatic cancer progression through tumor cell migration and angiogenesis. Because T22 suppressed the migration of both pancreatic cancer cells and endothelial cells in vitro, additional in vivo studies are warranted to examine whether T22 suppresses the tumor spread and tumor angiogenesis to clarify the role of the SDF-1/CXCR4 receptor ligand system in pancreatic cancer.
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FOOTNOTES |
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1 Supported in part by a grant from the Japanese
Ministry of Education. 
2 To whom requests for reprints should be
addressed, at Department of Surgery, Kishiwada City Hospital,
2-Gakuhara-cho, Kishiwada-shi, Osaka 596-8501, Japan. Phone:
81-75-751-3650; Fax: 81-75-751-3219.
3 The abbreviations used are: IL, interleukin;
SDF-1, stromal cell-derived factor 1; RT-PCR, reverse
transcription-PCR; FBS, fetal bovine serum; HUVEC, human umbilical vein
endothelial cell.
Received 5/20/99; revised 3/ 1/00; accepted 6/ 6/00.
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 J. Heidemann, H. Ogawa, P. Rafiee, N. Lugering, C. Maaser, W. Domschke, D. G. Binion, and M. B. Dwinell Mucosal angiogenesis regulation by CXCR4 and its ligand CXCL12 expressed by human intestinal microvascular endothelial cells Am J Physiol Gastrointest Liver Physiol, June 1, 2004; 286(6): G1059 - G1068. [Abstract] [Full Text] [PDF]
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S. Tavor, I. Petit, S. Porozov, A. Avigdor, A. Dar, L. Leider-Trejo, N. Shemtov, V. Deutsch, E. Naparstek, A. Nagler, et al. CXCR4 Regulates Migration and Development of Human Acute Myelogenous Leukemia Stem Cells in Transplanted NOD/SCID Mice Cancer Res., April 15, 2004; 64(8): 2817 - 2824. [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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 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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X. Chen, J. A. Beutler, T. G. McCloud, A. Loehfelm, L. Yang, H.-F. Dong, O. Y. Chertov, R. Salcedo, J. J. Oppenheim, and O. M. Z. Howard Tannic Acid Is an Inhibitor of CXCL12 (SDF-1{alpha})/CXCR4 with Antiangiogenic Activity Clin. Cancer Res., August 1, 2003; 9(8): 3115 - 3123. [Abstract] [Full Text] [PDF]
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Y. Ding, Y. Shimada, M. Maeda, A. Kawabe, J. Kaganoi, I. Komoto, Y. Hashimoto, M. Miyake, H. Hashida, and M. Imamura Association of CC Chemokine Receptor 7 with Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma Clin. Cancer Res., August 1, 2003; 9(9): 3406 - 3412. [Abstract] [Full Text] [PDF]
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I. S. Zeelenberg, L. Ruuls-Van Stalle, and E. Roos The Chemokine Receptor CXCR4 Is Required for Outgrowth of Colon Carcinoma Micrometastases Cancer Res., July 1, 2003; 63(13): 3833 - 3839. [Abstract] [Full Text] [PDF]
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 R. J. Phillips, M. D. Burdick, M. Lutz, J. A. Belperio, M. P. Keane, and R. M. Strieter The Stromal Derived Factor-1/CXCL12-CXC Chemokine Receptor 4 Biological Axis in Non-Small Cell Lung Cancer Metastases Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1676 - 1686. [Abstract] [Full Text] [PDF]
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G. Helbig, K. W. Christopherson II, P. Bhat-Nakshatri, S. Kumar, H. Kishimoto, K. D. Miller, H. E. Broxmeyer, and H. Nakshatri NF-{kappa} B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4 J. Biol. Chem., June 6, 2003; 278(24): 21631 - 21638. [Abstract] [Full Text] [PDF]
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 J. M. Hall and K. S. Korach Stromal Cell-Derived Factor 1, a Novel Target of Estrogen Receptor Action, Mediates the Mitogenic Effects of Estradiol in Ovarian and Breast Cancer Cells Mol. Endocrinol., May 1, 2003; 17(5): 792 - 803. [Abstract] [Full Text] [PDF]
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S. Barbero, R. Bonavia, A. Bajetto, C. Porcile, P. Pirani, J. L. Ravetti, G. L. Zona, R. Spaziante, T. Florio, and G. Schettini Stromal Cell-derived Factor 1{alpha} Stimulates Human Glioblastoma Cell Growth through the Activation of Both Extracellular Signal-regulated Kinases 1/2 and Akt Cancer Res., April 15, 2003; 63(8): 1969 - 1974. [Abstract] [Full Text] [PDF]
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P. Lu, Y. Nakamoto, Y. Nemoto-Sasaki, C. Fujii, H. Wang, M. Hashii, Y. Ohmoto, S. Kaneko, K. Kobayashi, and N. Mukaida Potential Interaction between CCR1 and Its Ligand, CCL3, Induced by Endogenously Produced Interleukin-1 in Human Hepatomas Am. J. Pathol., April 1, 2003; 162(4): 1249 - 1258. [Abstract] [Full Text] [PDF]
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 J. L. Pablos, B. Santiago, M. Galindo, C. Torres, M. T. Brehmer, F. J. Blanco, and F. J. Garcia-Lazaro Synoviocyte-Derived CXCL12 Is Displayed on Endothelium and Induces Angiogenesis in Rheumatoid Arthritis J. Immunol., February 15, 2003; 170(4): 2147 - 2152. [Abstract] [Full Text] [PDF]
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G. P. Schneider, R. Salcedo, H. F. Dong, H. K. Kleinman, J. J. Oppenheim, and O. M. Z. Howard Suradista NSC 651016 Inhibits the Angiogenic Activity of CXCL12-Stromal Cell-derived Factor 1{alpha} Clin. Cancer Res., December 1, 2002; 8(12): 3955 - 3960. [Abstract] [Full Text] [PDF]
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J. Eddleston, S. C. Christiansen, and B. L. Zuraw Functional Expression of the C-X-C Chemokine Receptor CXCR4 by Human Bronchial Epithelial Cells: Regulation by Proinflammatory Mediators J. Immunol., December 1, 2002; 169(11): 6445 - 6451. [Abstract] [Full Text] [PDF]
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K. Dunussi-Joannopoulos, K. Zuberek, K. Runyon, R. G. Hawley, A. Wong, J. Erickson, S. Herrmann, and J. P. Leonard Efficacious immunomodulatory activity of the chemokine stromal cell-derived factor 1 (SDF-1): local secretion of SDF-1 at the tumor site serves as T-cell chemoattractant and mediates T-cell-dependent antitumor responses Blood, August 13, 2002; 100(5): 1551 - 1558. [Abstract] [Full Text] [PDF]
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D. Milliken, C. Scotton, S. Raju, F. Balkwill, and J. Wilson Analysis of Chemokines and Chemokine Receptor Expression in Ovarian Cancer Ascites Clin. Cancer Res., April 1, 2002; 8(4): 1108 - 1114. [Abstract] [Full Text] [PDF]
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 K. Kawakami, M. Kawakami, P. J. Snoy, S. R. Husain, and R. K. Puri In Vivo Overexpression of IL-13 Receptor {alpha}2 Chain Inhibits Tumorigenicity of Human Breast and Pancreatic Tumors in Immunodeficient Mice J. Exp. Med., December 17, 2001; 194(12): 1743 - 1754. [Abstract] [Full Text] [PDF]
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C. J. Scotton, J. L. Wilson, D. Milliken, G. Stamp, and F. R. Balkwill Epithelial Cancer Cell Migration: A Role for Chemokine Receptors? Cancer Res., July 1, 2001; 61(13): 4961 - 4965. [Abstract] [Full Text] [PDF]
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, the condition containing no
stimulatory factors (medium only in the lower well); 
, the condition
containing a stimulatory factor (100 ng/ml SDF-1 or MRC-9 in the lower
well); 
, the condition containing both stimulatory and
inhibitory factors 1 µM T22 or 10 µg/ml IVR7).
Mean ± SEM (n = 3). *,
significant increase versus control
(P < 0.05, t test). 
, significant
inhibition by T22 or IVR7 (P < 0.05).