Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kitadai, Y.
Right arrow Articles by Tahara, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kitadai, Y.
Right arrow Articles by Tahara, E.
Clinical Cancer Research Vol. 6, 2735-2740, July 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Regulation of Disease-Progression Genes in Human Gastric Carcinoma Cells by Interleukin 81

Yasuhiko Kitadai2, Ken Haruma, Naofumi Mukaida, Yasukazu Ohmoto, Norimasa Matsutani, Wataru Yasui, Shigeru Yamamoto, Koji Sumii, Goro Kajiyama, Isaiah J. Fidler and Eiichi Tahara

First Departments of Internal Medicine [Y. K., K. H., N. M., S. Y., K. S., G. K.] and Pathology [W. Y., E. T.], Hiroshima University School of Medicine, Hiroshima 734-8551, Japan; Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan [N. M.]; Cellular Technology Institute, Otsuka Pharmaceutical Company, Ltd., Tokushima 771-01, Japan [Y. O.]; and Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [I. J. F.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The expression of interleukin 8 (IL-8) by human gastric carcinomas directly correlates with tumor vascularity and disease progression. To determine whether IL-8 can act in an autocrine manner to regulate the expression of other disease-progression genes, we examined the expression of IL-8 receptors IL-8RA (CXCR1) and IL-8RB (CXCR2) in six different human gastric carcinoma cell lines and 38 surgical specimens of human gastric carcinomas. All of the gastric carcinoma cell lines expressed mRNA and protein for IL-8RA and IL-8RB protein. In all surgical specimens, the majority of the tumor cells and small vessel endothelial cells stained positive for IL-8RA and IL-8RB protein. In vitro treatment of human gastric cancer MKN-1 cells with exogenous IL-8 enhanced the expression of epidermal growth factor receptor, type IV collagenase (metalloproteinase-9), vascular endothelial growth factor, and IL-8 mRNA. In contrast, treatment with exogenous IL-8 decreased expression of E-cadherin mRNA. IL-8 treatment increased invasive capacity of MKN-1 cells, which was associated with activity of metalloproteinase-9. Collectively, these results demonstrate that human gastric carcinoma cells express receptors for IL-8 and that IL-8 may play a role in the progressive growth of human gastric carcinoma by autocrine/paracrine mechanisms.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
IL3 -8, a member of the CXC chemokine family, was initially shown to be a chemoattractant for neutrophils and lymphocytes (1 , 2) . Subsequent studies revealed that IL-8 can also induce haptotatic migration of tumor cells (3) , proliferation of keratinocytes and melanoma cells (4 , 5) , and angiogenesis (6 , 7) . Indeed, human recombinant IL-8 has been shown to induce proliferation and migration of human umbilical vein endothelial cells, and its stimulation of vascularization in the rat cornea assay (7) has led to its implication in the induction of angiogenesis in such diverse diseases as psoriasis (8) , rheumatoid arthritis (9) , idiopathic pulmonary fibrosis (10) , and some neoplasms (11 , 12) . We have recently reported that most gastric cancer cell lines express IL-8 mRNA and protein (11) . Gastric cancer cells in surgical specimens of human gastric carcinomas overexpress IL-8 compared with corresponding normal mucosa, and the IL-8 mRNA level directly correlated with the vascularity of the tumors (11) . Furthermore, transfection of gastric carcinoma cells with the IL-8 gene enhanced their tumorigenic and angiogenic potential in the gastric wall of nude mouse (12) .

To determine whether IL-8 can interact with gastric cancer cells in an autocrine manner, we examined the presence and level of two distinct human IL-8 receptors: IL-8RA (CXCR1) and IL-8RB (CXCR2) (13 , 14) . The deduced amino acid sequences of both receptors predict that they belong to a family of seven transmembrane G protein-coupled receptors (15) . IL-8RA and IL-8RB bind to IL-8 with high affinity, although IL-8RB also binds to melanocyte growth-stimulatory activity and neutrophil-activating peptide 2 (16) . IHC analyses revealed that both IL-8 receptors are expressed on the surface of human carcinoma cells (17 , 18) , but the role of these receptors in cancer progression remains unknown.

In this study, we examined the expression of IL-8RA and RB in human gastric carcinoma cell lines and surgical specimens. We also examined the effects of IL-8 on the expression of disease-progression genes by treating gastric carcinoma cell lines with recombinant IL-8. Our studies clearly demonstrate that gastric carcinoma cells express both IL-8RA and IL-8RB and that the IL-8 receptor system may play a role in the processes of invasion and metastasis.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cell Cultures and Tumor Tissues.
Six cell lines established from human gastric carcinomas were maintained in RPMI 1640 (Nissui Co., Ltd., Tokyo, Japan) with 10% fetal bovine serum (M. A. Bioproducts, Inc., Walkersville, MD). The TMK-1 cell line (poorly differentiated adenocarcinoma) was established in our laboratory (19) . The other five gastric carcinoma cell lines (MKN-1, adenosquamous carcinoma; MKN-7, MKN-28, and MKN-74, well-differentiated adenocarcinomas; and MKN-45, poorly differentiated adenocarcinoma) were provided by Dr. T. Suzuki (Fukushima Medical College, Fukushima, Japan).

A total of 38 cases of gastric carcinoma, all assessed by Hiroshima University School of Medicine, were examined. The definition of stage grouping and the histological classification were made according to the criteria of the Japanese Research Society for Gastric Cancer (20) .

RT-PCR.
Total RNA was extracted from human gastric carcinoma cell lines using RNAzol B (Cinna/Biotex, Houston, TX) according to the manufacturer’s instructions. Two pairs of oligomers were synthesized based on the reported sequences of human IL-8 receptors (5'-CATGTCAAATATTACAGATCC-3' and 5'-TACTTGTTGAGTGTCTCAGTTT-3' for IL-8RA and 5'-CATGGAGAGTGACAGCTTTGA-3' and 5'-ACTTGTTGATTTCCAGGGATT-3' for IL-8RB) (13 , 14) . RT-PCR was performed using the obtained RNA and the oligomers as templates and primers, respectively (21) . The cDNA was amplified by 30 PCR cycles, and the thermal cycle profile was: denaturation for 2 min at 94°C, annealing for 2 min at 55°C, and extension for 3 min at 72°C. After the reaction, the mixtures were loaded onto a 5% nondenaturing polyacrylamide gel in Tris-borate-EDTA buffer. RT-PCR reaction without the reverse transcriptase showed no specific band.

IL-8 Treatment of Gastric Carcinoma Cells.
After 24 h of serum starvation, 10 ng/ml IL-8 (Otsuka, Tokushima, Japan) was added to the cultures. The six gastric carcinoma cells were treated for 0 (control), 3, and 24 h. Five micrograms of polyadenylated RNA were subjected to Northern blot analysis.

Northern Blot Analysis.
Polyadenylated mRNA was extracted from gastric carcinoma cell lines and surgical specimens using the FastTrack mRNA isolation kit (Invitrogen Co., San Diego, CA). mRNA was electrophoresed on a 1% denaturing formaldehyde/agarose gel, electrotransferred at 0.6 A to a GeneScreen nylon membrane (DuPont Co., Boston, MA), and UV cross-linked with 120,000 mJ/cm2 using a UV Stratalinker 1800 (Stratagene, La Jolla, CA). Hybridizations were performed as described previously (22) . Nylon filters were washed at 65°C with 30 mM NaCl, 3 mM sodium citrate (pH 7.2), and 0.1% SDS (w/v).

The cDNA probes used in these analyses were a 0.5-kb human IL-8 cDNA probe, a 1.1-kb human type IV collagenase cDNA probe (kindly provided by Dr. W. G. Stetler-Stevenson, NIH, Bethesda, MD), a 0.6-kb mouse E-cadherin cDNA probe (kindly provided by Dr. M. Takeichi, Kyoto University, Kyoto, Japan), a 2.4-kb human EGFR cDNA probe (purchased from Health Science Research Resources Bank, Osaka, Japan), and a 0.7-kb human VEGF cDNA probe (kindly provided by Dr. M. Shibuya, University of Tokyo, Tokyo, Japan). The ß-actin cDNA probe and glyceraldehyde-3-phosphate dehydrogenase cDNA probes were purchased from Oncor, Inc. (Gaithersburg, MD) and Clontech Inc. (Palo Alto, CA), respectively. Each cDNA fragment was purified by agarose gel electrophoresis, recovered using GeneClean (BIO 101, Inc., La Jolla, CA), and radiolabeled using the random primer technique with 32P-labeled deoxyribonucleotide triphosphates (23) .

IHC Staining.
Archival paraffin blocks of 38 cases were available. Consecutive 4-µm sections were cut from each study block. Sections were immunostained for IL-8RA and RB. IHC staining was performed by the immunoperoxidase technique with minor modifications (17 , 18) . IL-8RA- and RB-specific antibodies (24) , which were rabbit polyclonal antibodies, were used at a 1:200 dilution. These antibodies react specifically with cytoplasmic domains of IL-8RA and IL-8RB but do not cross-react with each other. The specificity of the reaction was determined as: (a) anti-IL-8RA and anti-IL-8RB antibodies were absorbed at 4°C overnight with excess GST proteins fused with extracellular domains of human IL-8RA and IL-8RB, respectively; and (b) nonimmune rabbit IgG was used in the primary reaction.

Gelatin Zymogram.
TMK-1 and MKN-1 cells were incubated with 10 ng/ml IL-8 (Otsuka) for 24 h in serum-free conditions. A total of 15 µl of the culture medium were applied to a 10% polyacrylamide gel containing 2 mg/ml gelatin. After electrophoresis, the gel was washed with washing buffer [50 mM Tris-HCl (pH 7.4) and 2.5% Triton X-100] at room temperature for 30 min and then placed in incubation buffer [30 mM Tris-HCl (pH 7.4), 0.2 M NaCl, 10 mM CaCl2, and 0.02% NaN3] at 37°C overnight. The gel was stained with 0.02% Coomassie brilliant blue in 20% methanol and 10% acetic acid and destained with 20% methanol and 10% acetic acid. Molecular weights of the gelatinolytic bands were estimated using molecular weight markers (Daiichi Pure Chemicals, Tokyo, Japan).

Invasion Assay.
Cultured cells were harvested by a brief exposure to 0.25% trypsin at 37°C. After centrifugation, cells were resuspended in medium and their invasive behavior was examined in an invasion chamber (Becton Dickinson, Bedford, MA). Cell viability was evaluated with the 0.1% trypan blue exclusion method. Transwell cell culture chambers with 8-mm diameter filters were used for this assay. The Matrigel-coated filters were placed on Boyden chambers, and the cells (5 x 105) suspended in RPMI medium were placed in the upper chamber. RPMI containing recombinant IL-8 was placed in the lower compartment of the Boyden chambers. The chambers were incubated in 5% CO2 at 37°C, and the cells in the lower compartment were counted hourly for 24 h. The assays were performed in triplicate.

Statistical Analysis.
The significance of the differences in in vitro data were analyzed by the unpaired Student’s t test (two-tailed).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Expression of IL-8 Receptors by Human Gastric Carcinoma Cell Lines and Gastric Carcinoma Tissues.
The expression of IL-8 receptor mRNA by gastric carcinoma cell lines was examined by RT-PCR analysis. Similar levels of transcript for IL-8RA and IL-8RB mRNA were detected in all of the gastric carcinoma cell lines (Fig. 1ACitation ), whereas IL-8 mRNA was expressed by five cell lines at various levels (Fig. 1BCitation ). The expression of IL-8 receptors was confirmed at the protein level by immunohistochemistry. Representative samples of the MKN-1 cells, shown in Fig. 2, A and BCitation , reveal that both IL-8RA and IL-8RB localized in the cell membrane. In some dividing cells, immunoreactivity for the receptors was also detected in cytosol. The expression of IL-8 receptors in 38 surgical specimens was examined by immunohistochemistry. In all surgical specimens, the majority of the tumor cells stained positive for IL-8RA and IL-8RB (representative examples, Fig. 2, C and DCitation ). Vascular endothelial cells and neutrophils also stained positive for the receptors (representative examples, Fig. 2, E and FCitation ). Faint immunoreactivity was also present in some fibroblasts and smooth muscle cells (data not shown). Heterogeneous staining was observed in several cases. Immunoreactivity of IL-8 receptors (A and B) in cancer cells was more intense at the invasive edge, where intense staining was found in cancer cells infiltrating lymphatic vessels (Fig. 2ECitation ).



View larger version (40K):
[in this window]
[in a new window]
  		Fig. 1. A, expression of mRNA for IL-8 receptor A and B by gastric carcinoma cell lines. RT-PCR was performed using the RNA obtained as described in "Materials and Methods." B, expression of IL-8 mRNA by gastric carcinoma cell lines. Northern blot analysis was performed by using 5 µg of polyadenylated selected RNA as described in "Materials and Methods." A glyceraldehyde-3-phosphate dehydrogenase probe was used as an internal control.

 


View larger version (141K):
[in this window]
[in a new window]
  		Fig. 2. Immunohistochemistry to identify expression of IL-8 receptor A (A, C, and E) and IL-8 receptor B (B, D, and F) in MKN-1 cells and surgical specimens of human gastric carcinomas. Immunoreactivity for both IL-8RA and IL-8RB was detected in the membrane and cytoplasm of MKN-1 cells (A and B) and in tumor cells in surgical tissues (C and D). The staining was more intense in cancer cells infiltrating lymphatic vessels (E, arrowheads). IL-8 receptor immunoreactivity was also present in vascular endothelial cells (E and F).

 
Effect of IL-8 on the Expression of Disease-Progression Genes in Human Gastric Carcinoma Cell Lines.
It has been reported that IL-8 can up-regulate collagenase expression in human cells (25) and influence the biology of liver and pancreas carcinoma cells (26) . IL-8 acts as an autocrine growth factor for liver and pancreas cancer (26) and melanoma cells (5) , but not gastric cancer cells (11) . We next examined the effect of exogenous IL-8 on the in vitro expression of disease-progression genes by gastric carcinoma cell lines. The expression of mRNA was examined by Northern blot analysis, and the expression level was quantified by densitometry of autoradiograms. The data are summarized in Table 1Citation , and representative examples are shown in Fig. 3ACitation . The expression of IL-8 mRNA by all of the six cell lines was apparently induced by IL-8 itself at 3 h after treatment. The expression of EGFR and VEGF mRNA by several cell lines was also increased at various levels. The expression of a 92-kDa type IV collagenase (MMP-9) was constitutively expressed by MKN-1 and MKN-7 cells and was increased by treatment with IL-8. On the other hand, 3 h after exposure to exogenous IL-8, the expression of E-cadherin mRNA in MKN-1 cells was transiently decreased (Fig. 3ACitation ). No expression of basic fibroblast growth factor and 72-kDa type IV collagenase (MMP-2) mRNA was detected in control or IL-8-treated cells (data not shown).


View this table:
[in this window]
[in a new window]
  		Table 1 Effect of IL-8 on the expression of the disease-progression genes in human gastric carcinomas

The numbers shown are the densitometric quantitation of the ratios of the area between the specific transcripts and the ß-actin transcript after treatment with IL-8, compared in each case with the respective control (the value for untreated cells with IL-8) defined as 1.0.

 


View larger version (58K):
[in this window]
[in a new window]
  		Fig. 3. Effect of IL-8 on the expression of the disease-progression genes in human gastric carcinomas. A, Northern blot analysis. Five micrograms of polyadenylated-selected RNA was subjected to Northern blot analysis, as described in "Materials and Methods". The signal intensity was measured by densitometric scanning. A ß-actin probe was applied as an internal control. B, gelatin zymogram. The media were collected and subjected to zymography, as described in "Materials and Methods." Collagenase activity in conditioned media from MKN-1 cells was apparently increased by treatment with IL-8.

 
Effect of IL-8 on Invasion of Gastric Carcinoma Cells.
We next analyzed whether the increased expression of MMP-9 mRNA by IL-8 treatment correlated with collagenase type IV activity and an increase in penetration through reconstituted basement membranes. We used the two representative cell lines, MKN-1 and TMK-1, for this experiment because enhanced expression of MMP-9 mRNA by IL-8 was observed in MKN-1 but not TMK-1. These cell lines were assayed for their potential to penetrate filters coated with Matrigel (Table 2)Citation . Treatment with IL-8 did not affect invasion of TMK-1 cells. In contrast, treatment with IL-8 significantly increased collagenase type IV activity (Fig. 3BCitation ) and the number of invading MKN-1 cells, agreeing with the above data that treatment with exogenous IL-8 increased collagenase type IV mRNA expression in MKN-1 but not TMK-1 cells (Fig. 3ACitation ).


View this table:
[in this window]
[in a new window]
  		Table 2 Effect of IL-8 on migration through Matrigel-coated filters

Transwell cell culture chambers with 8-mm diameter filters were used for this assay. The Matrigel-coated filters were placed on Boyden chambers, and cells (1 x 105) suspended in serum-free RPMI medium were placed in the upper chamber. RPMI containing recombinant IL-8 was placed in the lower compartment of the Boyden chambers. The cells in the lower compartment were counted after 24 h. Values are mean ± SD of triplicate cultures. This is one representative experiment of three.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we examined the expression of IL-8 receptors in human gastric carcinomas. Both IL-8RA and IL-8RB were constitutively expressed by all human gastric cancer cell lines examined. IHC analysis of surgical specimens of human gastric carcinomas showed that IL-8 receptors were expressed by tumor cells, microvascular endothelial cells, and inflammatory cells. IL-8 is expressed by a variety of malignant tumor cells, including pancreas (26) , lung (27) , prostate (28) , bladder (29) , head and neck squamous carcinomas (30) , and melanoma (5) . IL-8 produced by lung carcinoma cells has actually been shown to stimulate angiogenesis (27 , 31) . More recently, IL-8 has been shown to act as an autocrine growth stimulator for lung (32) , liver, and pancreatic carcinomas (26) , and melanoma cells (5 , 33) . Our recent data have revealed that IL-8 mRNA levels in gastric carcinoma tissues directly correlated with tumor vascularity (11) , and transfection of the IL-8 gene into gastric carcinoma cells enhanced tumorigenicity and angiogenesis after implantation of these cells into the gastric wall (orthotopic site) of nude mice (12) . Collectively, these data suggest that IL-8 is an important regulator of angiogenesis in gastric carcinoma.

The IL-8 receptors IL-8RA and IL-8RB bind IL-8 with high affinity and act via G proteins through the phospholipase C pathway, which induces the release of intracellular calcium and the activation of protein kinase C (13) . The affinity of IL-8 for the IL-8RB (kDa = 0.031–0.133 nM) is two to five times greater than the affinity for IL-8RA (kDa = 0.096–0.168; Ref. 16 ). Microvessel endothelial cells in human head and neck squamous cell carcinomas have been shown to express IL-8RA and IL-8RB (17) , as do inflammatory cells, keratinocytes, smooth muscle cells, and fibroblasts (24) . Differential expression of the two receptors on SVECs and LVECs was reported for human breast carcinoma tissues (18) . Whereas IL-8RB was expressed prominently on both SVECs and LVECs, IL-8RA was present in only 25% of the SVECs and 14% of the LVECs (18) . Our demonstration that microvessel endothelial cells in human gastric carcinomas express both IL-8 receptors expand these observations and suggest that IL-8, indeed, plays a role in angiogenesis of these cancers.

The metastatic potential of neoplasms has been correlated with the expression level of several independent genes that regulate, among others, cell growth, angiogenesis, invasion, motility, and adhesion (34) . Our study revealed that treatment of MKN-1 cells with IL-8 enhanced the expression of EGFR (proliferation), IL-8, and VEGF (angiogenesis), and collagenase type IV (invasion), whereas the expression of E-cadherin (cohesion) was decreased (Fig. 3ACitation ). Furthermore, IL-8 increased MMP-9 activity (Fig. 3BCitation ) and invasion through Matrigel of some, but not all, gastric carcinoma cells (Table 2)Citation .

The growth and spread of tumor cells depends on adequate vasculature (35, 36, 37) . Invasion of the host stroma and degradation of the blood vessel basement membrane are necessary for metastasis (38 , 39) . The expression of E-cadherin, which is directly related to cell-to-cell cohesion, is inversely correlated with progression and metastasis (40) . Thus, a simultaneous increase in the expression of EGFR (growth), VEGF (angiogenesis), and type IV collagenase (invasion) and decrease in the expression of E-cadherin (adhesion) should enhance metastatic potential of cancer cells. IL-8RA and IL-8RB expression was similar on the gastric carcinoma cell lines examined, however, response to IL-8 was different among these cell lines. In contrast to MKN-1 cells, the expression of disease-progression genes (except IL-8) by TMK-1 cells was not affected by treatment with IL-8 (Fig. 3)Citation . To elucidate the mechanism of differential response to IL-8 by these two cell lines and which receptor is more responsible for the behavior, additional studies concerning signal transduction of IL-8 receptors using several cell lines are necessary.

In summary, gastric carcinoma cells express both IL-8 and its receptors. The IL-8 receptor system regulates expression of disease-progression genes in human gastric cancer cells and may be involved in cancer metastasis and, hence, should be a target for therapy.


   ACKNOWLEDGMENTS
 
We thank Walter Pagel for critical editorial comments and Lola López for expert assistance in the preparation of this manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, Sports and Culture, Japan and from the Ministry of Health and Welfare of Japan (to Y. K. and K. H., Grant 10-13); and by Cancer Center Support Core Grant CA16672 and Grant R35-CA42107 (to I. J. F.) from the National Cancer Institute, NIH. Back

2 To whom requests for reprints should be addressed, at First Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Back

3 The abbreviations used are: IL, interleukin; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; MMP, metalloproteinase; RT-PCR, reverse transcription-PCR; IHC, immunohistochemical; SVEC, small vessel endothelial cell; LVEC, large VEC. Back

Received 8/23/99; revised 3/17/00; accepted 3/27/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Matsushima K., Morishita K., Yoshimura T., Lavu S., Kobayashi Y., Lew W., Appella E., Kung H. F., Leonard E. J., Oppenheim J. J. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin-1 and tumor necrosis factor. J. Exp. Med., 167: 1883-1893, 1988.[Abstract/Free Full Text]
  2. Matsushima K., Baldwin E. T., Mukaida N. Interleukin-8 and MCAF: novel leukocyte recruitment and activity cytokines. Chem. Immunol., 51: 236-265, 1992.[Medline]
  3. Wang J. M., Taraboletti G., Matsushima K., Damme J. V., Mantovani A. Induction of haptotatic migration of melanoma cells by neutrophil activating protein/IL-8. Biochem. Biophys. Res. Commun., 169: 165-170, 1990.[CrossRef][Medline]
  4. Krueger G., Jorgensen C., Miller C., Schroeder J., Sticherling M., Christopher E. Effect of IL-8 on epidermal proliferation. J. Invest. Dermatol., 94: 545-552, 1990.
  5. Schandendorf D., Moller A., Algermissen B., Worm M., Sticherling M., Czarnetzki B. M. IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J. Immunol., 151: 2667-2675, 1993.[Abstract]
  6. Koch A. E., Polverini P. S., Kunkel S. L., Harlow L. A., DiPietro L. A., Elner S. G., Strieter R. M. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science (Washington DC), 258: 1798-1801, 1992.[Abstract/Free Full Text]
  7. Strieter R. M., Kunkel S. L., Elner V. M., Martonyi C. L., Koch A. E., Polverini P. J., Elner S. G. Interleukin-8: a corneal factor that induces neovascularization. Am. J. Pathol., 141: 1279-1284, 1992.[Abstract]
  8. Schroeder J-M., Christopher E. Identification of C5ades arg and an anionic neutrophil-activating peptide (ANAP) in psoriatic scales. J. Invest. Dermatol., 87: 53-58, 1986.[CrossRef][Medline]
  9. de Marco D., Kunkel S. L., Strieter R. M., Basha M., Zurier R. B. Interleukin-1-induced gene expression of neutrophil activating protein (interleukin-8) and monocyte chemotactic peptide in human synovial cells. Biochem. Biophys. Res. Commun., 174: 411-416, 1991.[CrossRef][Medline]
  10. Keane M. P., Arenberg D. A., Lynch J. P., III, Whyte R. I., Iannettoni M. D., Burdick M. D., Wilke C. A., Morris S. B., Glass M. C., DiGiovine B., Kunkel S. L., Strieter R. M. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J. Immunol., 159: 1437-1443, 1997.[Abstract]
  11. Kitadai Y., Haruma K., Sumii K., Yamamoto S., Ue T., Yokozaki H., Yasui W., Ohmoto Y., Kajiyama G., Fidler I. J., Tahara E. Expression of interleukin-8 correlates with vascularity in human gastric carcinomas. Am. J. Pathol., 152: 93-100, 1998.[Abstract]
  12. Kitadai Y., Takahashi Y., Haruma K., Naka K., Sumii K., Yokozaki H., Yasui W., Mukaida N., Ohmoto Y., Kajiyama G., Fidler I. J., Tahara E. Transfection of interleukin-8 increases angiogenesis and tumorigenesis of human gastric carcinoma cells in nude mice. Br. J. Cancer, 81: 647-653, 1999.[CrossRef][Medline]
  13. Holmes W. E., Lee J., Kuang W-J., Rice G. C., Wood W. I. Structure and functional expression of a human interleukin-8 receptor. Science (Washington DC), 253: 1278-1280, 1991.[Abstract/Free Full Text]
  14. Murphy P. E., Tiffany H. E. Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science (Washington DC), 253: 1280-1283, 1991.[Abstract/Free Full Text]
  15. Thelen M., Peveri P., Kernen P., von Tscharner V., Walz A., Baggiolini M. Mechanism of neutrophil activation by NAF, a novel monocyte-derived peptide agonist. FASEB J., 2: 2702-2706, 1995.[Abstract]
  16. Chutharapai A., Kim K. Regulation of the expression of IL-8 receptor A/B by IL-8: Possible function of each receptor. J. Immunol., 155: 2587-2594, 1995.[Abstract]
  17. Richards B. L., Eisma R. J., Spiro J. D., Lindquist R. L., Kreutzer D. L. Coexpression of interleukin-8 receptors in head and neck squamous cell carcinoma. Am. J. Surg., 174: 507-512, 1997.[CrossRef][Medline]
  18. Miller L. J., Kurtzman S. H., Wang Y., Anderson K. H., Lindquist R. R., Kreutzer D. L. Expression of interleukin-8 receptors on tumor cells and vascular endothelial cells in human breast cancer tissues. Anticancer Res., 18: 77-82, 1998.[Medline]
  19. Ochiai A., Yasui W., Tahara E. Growth-promoting effect of gastrin in human gastric carcinoma cell line TMK-1. Jpn. J. Cancer Res., 76: 1064-1071, 1985.[Medline]
  20. Japanese Research Society for Gastric Cancer. Japanese Classification of Gastric Carcinoma. Tokyo: Kanehara, 1995.
  21. Sambrook, J., Fritsch, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual, Ed. 2. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 1989.
  22. Radinsky R., Kraemer P. M., Raines M. A., Kung H. J., Culp L. A. Amplification and rearrangement of Kirsten ras oncogene in virus transformed BALB/3T3 cells during malignant tumor progression. Proc. Natl. Acad. Sci. USA, 84: 5143-5147, 1987.[Abstract/Free Full Text]
  23. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem., 132: 6-13, 1983.[CrossRef][Medline]
  24. Morohashi H., Miyawaki T., Nomura H., Kuno K., Murakami S., Matsushima K., Mukaida N. Expression of both types of human interleukin-8 receptors on mature neutrophils, monocytes, and natural killer cells. J. Leukoc. Biol., 57: 180-187, 1995.[Abstract]
  25. Luca M., Huang S., Gershenwald J. E., Singh R. K., Reich R., Bar-Eli M. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am. J. Pathol., 151: 1105-1113, 1997.[Abstract]
  26. Miyamoto M., Shimizu Y., Okada K., Kashii Y., Higuchi K., Watanabe A. Effect of interleukin-8 on production of tumor-associated substances and autocrine growth of human liver and pancreatic cancer cells. Cancer Immunol. Immunother., 47: 47-57, 1998.[CrossRef][Medline]
  27. Strieter R. M., Polverini P. J., Arenberg D. A., Walz A., Opdenakker G., Van-Damme J., Kunkel S. L. Role of C-X-C chemokines as regulators of angiogenesis in lung cancer. J. Leukoc. Biol., 57: 752-762, 1995.[Abstract]
  28. Green G. F., Kitadai Y., Pettaway C. A., von Eschenbach A. C., Bucana C. D., Fidler I. J. Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique. Am. J. Pathol., 150: 1571-1582, 1997.[Abstract]
  29. Tachibana M., Miyakawa A., Nakashima J., Murai M., Nakamura K., Kubo A., Hata J. I. Constitutive production of multiple cytokines and a human chorionic gonadotrophin ß-subunit by a human bladder cancer cell line (KU-19-19): possible demonstration of totipotential differentiation. Br. J. Cancer, 76: 163-174, 1997.[Medline]
  30. Richards B. L., Eisma R. J., Spiro J. D., Lindquist R. L., Kreutzer D. L. Coexpression of interleukin-8 receptors in head and neck squamous cell carcinoma. Am. J. Surg., 174: 507-512, 1997.
  31. Smith D. R., Polverini P. J., Kunkel S. L., Orringer M. B., Whyte R. I., Burdick M. D., Wilke C. A., Strieter R. M. Inhibition of interleukin-8 attenuates angiogenesis in bronchogenic carcinoma. J. Exp. Med., 179: 1409-1415, 1994.[Abstract/Free Full Text]
  32. Arenberg D. A., Kunkel S. L., Polverini P. J., Glass M., Burdick M. D., Strieter R. M. Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. J. Clin. Invest., 97: 2792-2802, 1996.[Medline]
  33. Singh R. K., Gutman M., Radinsky R., Bucana C. D., Fidler I. J. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res., 54: 3242-3247, 1994.[Abstract/Free Full Text]
  34. Fidler I. J. Critical factors in the biology of human cancer metastasis: twenty-eighth GHA Clowes Memorial Award Lecture. Cancer Res., 50: 6130-6138, 1990.[Abstract/Free Full Text]
  35. Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? GHA Clowes Memorial Award Lecture. Cancer Res., 46: 467-473, 1986.[Free Full Text]
  36. Folkman J. What is the evidence that tumors are angiogenesis-dependent?. J. Natl. Cancer Inst., 82: 4-6, 1990.[Free Full Text]
  37. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N. Engl. J. Med., 324: 1-8, 1991.[Abstract]
  38. Liotta L. A. Tumor invasion and metastasis: role of the extracellular matrix—Rhoads Memorial Award Lecture. Cancer Res., 46: 1-7, 1986.[Free Full Text]
  39. Stetler-Stevenson W. G. Type IV collagenase in tumor invasion and metastasis. Cancer Metastasis Rev., 9: 289-303, 1990.[CrossRef][Medline]
  40. Frixen U. H., Behrens J., Sachs M., Eberle G., Voss B., Warda A., Lochner D., Birchmeier W. E. Cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J. Cell Biol., 113: 173-185, 1991.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Cell Physiol.Home page
C. R. Amura, K. S. Brodsky, B. Gitomer, K. McFann, G. Lazennec, M. T. Nichols, A. Jani, R. W. Schrier, and R. Brian Doctor
CXCR2 agonists in ADPKD liver cyst fluids promote cell proliferation
Am J Physiol Cell Physiol, March 1, 2008; 294(3): C786 - C796.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
B.-R. Lin, C.-C. Chang, L.-R. Chen, M.-H. Wu, M.-Y. Wang, I-H. Kuo, C.-Y. Chu, K.-J. Chang, P.-H. Lee, W.-J. Chen, et al.
Cysteine-Rich 61 (CCN1) Enhances Chemotactic Migration, Transendothelial Cell Migration, and Intravasation by Concomitantly Up-Regulating Chemokine Receptor 1 and 2
Mol. Cancer Res., November 1, 2007; 5(11): 1111 - 1123.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
B. Wang, D. T. Hendricks, F. Wamunyokoli, and M. I. Parker
A Growth-Related Oncogene/CXC Chemokine Receptor 2 Autocrine Loop Contributes to Cellular Proliferation in Esophageal Cancer.
Cancer Res., March 15, 2006; 66(6): 3071 - 3077.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
S. A. Savage, L. Hou, J. Lissowska, W.-H. Chow, W. Zatonski, S. J. Chanock, and M. Yeager
Interleukin-8 polymorphisms are not associated with gastric cancer risk in a polish population.
Cancer Epidemiol. Biomarkers Prev., March 1, 2006; 15(3): 589 - 591.
[Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
A. Taguchi, N. Ohmiya, K. Shirai, N. Mabuchi, A. Itoh, Y. Hirooka, Y. Niwa, and H. Goto
Interleukin-8 Promoter Polymorphism Increases the Risk of Atrophic Gastritis and Gastric Cancer in Japan
Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2487 - 2493.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
W.-P. Lee, D.-I. Tai, K.-H. Lan, A. F.-Y. Li, H.-C. Hsu, E.-J. Lin, Y.-P. Lin, M.-L. Sheu, C.-P. Li, F.-Y. Chang, et al.
The -251T Allele of the Interleukin-8 Promoter Is Associated with Increased Risk of Gastric Carcinoma Featuring Diffuse-Type Histopathology in Chinese Population
Clin. Cancer Res., September 15, 2005; 11(18): 6431 - 6441.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
S. A. Savage, C. C. Abnet, S. D. Mark, Y.-L. Qiao, Z.-W. Dong, S. M. Dawsey, P. R. Taylor, and S. J. Chanock
Variants of the IL8 and IL8RB Genes and Risk for Gastric Cardia Adenocarcinoma and Esophageal Squamous Cell Carcinoma
Cancer Epidemiol. Biomarkers Prev., December 1, 2004; 13(12): 2251 - 2257.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
N. Mukaida
Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases
Am J Physiol Lung Cell Mol Physiol, April 1, 2003; 284(4): L566 - L577.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
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]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kitadai, Y.
Right arrow Articles by Tahara, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kitadai, Y.
Right arrow Articles by Tahara, E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online