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2008 Integrin alpha v beta 6 mediates the potential for colon cancer cells to colonize in and metastasize to the liver

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doi: 10.1111/j.1349-7006.2008.00762.xCancer Sci| May 2008|vol. 99|no. 5|879–887

© 2008 Japanese Cancer Association

Blackwell Publishing Asia

Integrin alphavbeta6 mediates the potential for colon

cancer cells to colonize in and metastasize to the liver

Guang-Yun Yang,1,2 Ke-Sen Xu,1 Zhong-Qing Pan,2 Zhao-Yang Zhang,1 Yue-Tang Mi,1 Jin-Shen Wang,1 Rong Chen3

and Jun Niu1,4

1General Surgical Department of Qilu Hospital and Institute of Hepatobiliary and Vascular Surgery, Shandong University, Jinan, 250012; 2Qingzhou People

Hospital of Shandong Province, 262500; 3Department of Pathophysiology, School of Medicine, Shandong University, Jinan, 250012 China

(Received August 11, 2007/Revised November 20, 2007; December 16 2007/Accepted December 24, 2007/Online publication February 21, 2008)

Integrin alphavbeta6 (ααααvββββ6) is correlated with colon cancer

progression. To detect the effects of ααααvββββ6 on liver metastasis, the

specificity of ααααvββββ6 against the monoclonal antibody (mAb) 2G2 was

examined by immunoprecipitation. Integrin ααααvββββ6-immunoreactivity

(IR) in liver metastasis tissues (63 cases) and colon carcinoma

(358 cases) were examined. These results showed that ααααvββββ6 was

specifically recognized by the mAb 2G2, and that rates of ααααvββββ6

positivity in liver metastatic tissues (71.4%, 45/63) were higher than

that for primary colon cancer (34.0%, 122/358) (

P <

0.01). Patients

who were ααααvββββ6-positive had higher liver metastasis rates (17%, 21/

122) than those who were ααααvββββ6-negative (only 3%, 7/236) (

P <

0.01).

To examine the underlying mechanisms associated with ααααvββββ6

regulating colonic metastasis in the liver, experimental liver

metastasis (intrasplenic injection of HT29 transfectants) and liver

colonization assays (direct injection of WiDr transfectants into the

liver) in nude mice were performed; these demonstrated that ααααvββββ6

contributed to the promotion of the metastatic potential and the

survival of cancer cells in the liver. Matrix metalloproteinase-9

(MMP-9) levels in the cultures of both HT29 and WiDr cells were

detected by the Biotrak MMP-9 activity assay system and gelatin

zymography assay, and showed that suppression of ααααvββββ6-IR

inhibited MMP-9 activity and secretion. Transwell migration assay

in

vitro

also showed that ααααvββββ6 promoted migration on fibronectin for

HT29/WiDr mock compared with HT29/WiDr antisense ββββ6 transfects

(

P <

0.01). We concluded that ααααvββββ6 may mediate the potential for

colon cancer cells to colonize in and metastasize to the liver. The

mechanisms that ααααvββββ6 may be involved in include the promotion of

MMP-9 secretion, the enhancement of migration on fibronectin, and

the survival of cancer cells in the liver. (

Cancer Sci

2008; 99: 879–887)

D

espite welcome declines in the mortality rate over the past

decade, the prevention of colonic metastasis to the liver in

patients with colon carcinoma remains one of the most challeng-

ing issues in cancer research. Surgical resection can provide a

potentially curative outcome, but nearly a quarter of patients

with colon carcinoma will develop a recurrence in the first 5

years, with about 40–50% accounting for liver metastasis.(1) The

conventional paradigm of liver metastasis in colon cancer is

based on a multistep tumor genesis model defined by a series of

progressive somatic genetic alterations, which give malignant cells

the ability to proceed through the many phases of metastasis.

When a colon carcinoma

in situ

develops into a metastatic

tumor in the liver, the degradation of extracellular matrix (ECM)

barriers by matrix metalloproteinase-9 (MMP-9), cell migratory

capability, and survival in a new environment, play important

roles in facilitating tumor cellular dissemination and metastasis.(2)

They are the common prerequisite conditions involved in liver

metastasis in colon cancer. It is well known that the expression

of MMPs is involved in liver metastasis in human colon

cancer.(3,4) MMP-9 is also named gelatinase B or Mr 92 000 type IV

collagenase, partly because of its ability to degrade type IV

collagen, the major structural component of basement membranes,

and because of the important role it is believed to play in

cellular invasion.(5) A change in the binding properties of

metastatic cells promotes their release from the stem tissue, cell

migration, and/or transport, and the homing of the target tissue.

Integrins are transmembrane glycoprotein receptors comprising

an alpha (α) and a beta (β) subunit in non-covalent association

that mediate dynamic linkages between the actin cytoskeleton

and the ECM as well as transducing signals to and from the cell

interior.(6,7) Within the αv subfamily, the αvβ6 subunit form

pivotal molecules involved in this progression.(8) Integrin αvβ6

is a fibronectin receptor expressed predominantly by epithelial

cells,(9) which is not expressed on normal epithelial cells;

however, it becomes highly expressed during tumorigenesis(10,11)

and de novo expression of αvβ6 has been observed in colon

cancer.(12) Integrin-mediated cell attachment, spreading, cell

migration, and tumor invasion were well known.(13,14) Bates

et al

.(15) reported that elevated αvβ6 expression facilitates the

invasion and dissemination of colon carcinoma cells, and

suggested that integrin αvβ6 created a tumor microenvironment

more amenable to progression. We have demonstrated that the

expression of αvβ6 results in MMP-9 secretion, demonstrating

a delicate balance between αvβ6 expression and MMP-9

levels.(16) Kawashima

et al

.(17) also reported that increased αvβ6

in gastric carcinoma is associated with lymph node metastasis.

However, the links between αvβ6 expressed in primary colon

cancer and both colonic liver colonization and colonic

metastasis to the liver remain unknown, and the mechanisms by

which integrin αvβ6 may mediate liver colonization and liver

metastasis are also unclear.

In this study, integrin-αvβ6 expression in hepatic metastatic

tissues and malignant colon carcinoma was examined by immuno-

histochemical (IHC) staining. A three-year follow-up for liver

metastasis of the patients with malignant colon carcinoma was

conducted. In addition, experimental liver metastatic assays

(intrasplenic injection of human colon cancer cell line, HT-29)

and liver colonization assays (direct injection of human colon

cancer cell line, WiDr, into the liver) on nude mice were per-

formed. MMP-9 levels in the cultures of both HT-29 and WiDr

transfectants were detected by the Biotrak MMP-9 activity assay

system and gelatin zymography. The migratory capabilites on

fibronectin of both HT-29 and WiDr transfectants

in vitro

were

detected by Transwell migration assay.

Materials and Methods

Cell lines and transfections.The human colon cancer cell lines

(SW480, HT29, and WiDr) and ras-transformed NIH 3T3 cells

were obtained from ATCC (Rockville, MD, USA) and maintained

as a monolayer in standard medium comprising Dulbecco’s

4To whom correspondence should be addressed.

E-mail: niujun1369@yahoo.com.cn


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