The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer

TY - JOUR

T1 - The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer

AU - Baker, Ann-Marie

AU - Cox, Thomas Robert

AU - Bird, Demelza

AU - Lang, Georgina

AU - Murray, Graeme I

AU - Sun, Xiao-Feng

AU - Southall, Stacey M

AU - Wilson, Jon R

AU - Erler, Janine T

PY - 2011/3/2

Y1 - 2011/3/2

N2 - Background: Emerging evidence implicates lysyl oxidase (LOX), an extracellular matrix-modifying enzyme, in promoting metastasis of solid tumors. We investigated whether LOX plays an important role in the metastasis of colorectal cancer (CRC). Methods: We analyzed LOX expression in a patient CRC tissue microarray consisting of normal colon mucosa (n = 49), primary (n = 510), and metastatic (n = 198) tissues. LOX was overexpressed in CRC cell line SW480 (SW480+LOX), and the expression was knocked down in CRC cell line SW620 using LOX-specific short hairpin RNA (SW620+shLOX). Effect of LOX manipulation on three-dimensional cell proliferation and invasion was characterized in vitro. Effect of LOX manipulation on tumor proliferation and metastasis was investigated in a subcutaneous tumor mouse model (n = 3 mice per group) and in an intrasplenic metastatic mouse model (n = 3 mice per group). The mechanism of LOX-mediated effects via v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) was investigated using dasatinib, an inhibitor of SRC activation. All statistical tests were two-sided. Results: Compared with normal colon tissue (n = 49), LOX expression was statistically significantly increased in tumor tissues (n = 510) of CRC patients (P <. 001), and a greater increase was observed in metastatic tissue (n = 198). SW480+LOX cells showed a statistically significantly increased three-dimensional proliferation (P =. 037) and invasion (P =. 015), whereas SW620+shLOX cells showed reduced proliferation (P =. 011) and invasion (P =. 013) compared with controls. Subcutaneous tumor growth in mice was statistically significantly increased in SW480+LOX tumors (P =. 036) and decreased in SW620+shLOX tumors (P =. 048), and metastasis was statistically significantly increased in SW480+LOX tumors (P =. 044) and decreased in SW620+shLOX tumors (SW620 control vs SW620+shLOX, mean = 1.0 luminescent signal, 95% confidence interval = 0.3 to 1.7 luminescent signal, vs mean = 0.3 luminescent signal, 95% confidence interval = 0.1 to 0.5 luminescent signal; P =. 035) compared with controls. LOX-mediated effects on tumor progression were associated with SRC activation, and these effects were inhibited by dasatinib. Conclusions: LOX showed an important role in CRC cell proliferation and metastasis and was dependent on the activation of SRC. These Results: have the potential to identify patients with high SRC activity, who may benefit from dasatinib treatment. The Author 2011. Published by Oxford University Press.2011

AB - Background: Emerging evidence implicates lysyl oxidase (LOX), an extracellular matrix-modifying enzyme, in promoting metastasis of solid tumors. We investigated whether LOX plays an important role in the metastasis of colorectal cancer (CRC). Methods: We analyzed LOX expression in a patient CRC tissue microarray consisting of normal colon mucosa (n = 49), primary (n = 510), and metastatic (n = 198) tissues. LOX was overexpressed in CRC cell line SW480 (SW480+LOX), and the expression was knocked down in CRC cell line SW620 using LOX-specific short hairpin RNA (SW620+shLOX). Effect of LOX manipulation on three-dimensional cell proliferation and invasion was characterized in vitro. Effect of LOX manipulation on tumor proliferation and metastasis was investigated in a subcutaneous tumor mouse model (n = 3 mice per group) and in an intrasplenic metastatic mouse model (n = 3 mice per group). The mechanism of LOX-mediated effects via v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) was investigated using dasatinib, an inhibitor of SRC activation. All statistical tests were two-sided. Results: Compared with normal colon tissue (n = 49), LOX expression was statistically significantly increased in tumor tissues (n = 510) of CRC patients (P <. 001), and a greater increase was observed in metastatic tissue (n = 198). SW480+LOX cells showed a statistically significantly increased three-dimensional proliferation (P =. 037) and invasion (P =. 015), whereas SW620+shLOX cells showed reduced proliferation (P =. 011) and invasion (P =. 013) compared with controls. Subcutaneous tumor growth in mice was statistically significantly increased in SW480+LOX tumors (P =. 036) and decreased in SW620+shLOX tumors (P =. 048), and metastasis was statistically significantly increased in SW480+LOX tumors (P =. 044) and decreased in SW620+shLOX tumors (SW620 control vs SW620+shLOX, mean = 1.0 luminescent signal, 95% confidence interval = 0.3 to 1.7 luminescent signal, vs mean = 0.3 luminescent signal, 95% confidence interval = 0.1 to 0.5 luminescent signal; P =. 035) compared with controls. LOX-mediated effects on tumor progression were associated with SRC activation, and these effects were inhibited by dasatinib. Conclusions: LOX showed an important role in CRC cell proliferation and metastasis and was dependent on the activation of SRC. These Results: have the potential to identify patients with high SRC activity, who may benefit from dasatinib treatment. The Author 2011. Published by Oxford University Press.2011

U2 - 10.1093/jnci/djq569

DO - 10.1093/jnci/djq569

M3 - Journal article

C2 - 21282564

SN - 1460-2105

VL - 103

SP - 407

EP - 424

JO - National Cancer Institute. Journal (Online)

JF - National Cancer Institute. Journal (Online)

IS - 5

ER -