Histopathological predictors of regional lymph node metastasis at the invasive front in early colorectal cancer

Akishima-Fukasawa, Yuri; Ishikawa, Yukio; Akasaka, Yoshikiyo; Uzuki, Miwa; Inomata, Naomi; Yokoo, Tomoko; Ishii, Ryuga; Shimokawa, Reiko; Mukai, Kiyoshi; Kiguchi, Hideko; Suzuki, Koyu; Fujiwara, Mieko; Ogata, Kentaro; Niino, Hitoshi; Sugiura, Hiroaki; Ichinose, Akihiro; Kuroda, Yoshikazu; Kuroda, Daisuke; Ishii, Toshiharu

doi:10.1111/j.1365-2559.2011.03964.x

Cited by 55 publications

(48 citation statements)

References 33 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, more recent reports suggest that ANGPTL4 may be proangiogenic and provascular permeability (23,25,(42)(43)(44)(45)(46). ANGPTL4 has been shown to disrupt vascular endothelial cellcell (tight and adherens) junctions, facilitating cellular transendothelial passage and tumor dissemination (47).…”

Section: Discussionmentioning

confidence: 99%

Hypoxic retinal Müller cells promote vascular permeability by HIF-1–dependent up-regulation of angiopoietin-like 4

Xin¹,

Rodrigues²,

Umapathi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

125

113

View full text Add to dashboard Cite

Vision loss from ischemic retinopathies commonly results from the accumulation of fluid in the inner retina [macular edema (ME)]. Although the precise events that lead to the development of ME remain under debate, growing evidence supports a role for an ischemia-induced hyperpermeability state regulated, in part, by VEGF. Monthly treatment with anti-VEGF therapies is effective for the treatment of ME but results in a major improvement in vision in a minority of patients, underscoring the need to identify additional therapeutic targets. Using the oxygen-induced retinopathy mouse model for ischemic retinopathy, we provide evidence showing that hypoxic Müller cells promote vascular permeability by stabilizing hypoxia-inducible factor-1α (HIF-1α) and secreting angiogenic cytokines. Blocking HIF-1α translation with digoxin inhibits the promotion of endothelial cell permeability in vitro and retinal edema in vivo. Interestingly, Müller cells require HIF-but not VEGF-to promote vascular permeability, suggesting that other HIF-dependent factors may contribute to the development of ME. Using gene expression analysis, we identify angiopoietinlike 4 (ANGPTL4) as a cytokine up-regulated by HIF-1 in hypoxic Müller cells in vitro and the ischemic inner retina in vivo. ANGPTL4 is critical and sufficient to promote vessel permeability by hypoxic Müller cells. Immunohistochemical analysis of retinal tissue from patients with diabetic eye disease shows that HIF-1α and ANGPTL4 localize to ischemic Müller cells. Our results suggest that ANGPTL4 may play an important role in promoting vessel permeability in ischemic retinopathies and could be an important target for the treatment of ME.diabetes | retinal vein occlusion | angiogenesis | transcription factor I schemic retinopathies include a diverse group of retinal diseases, in which immature retinal vasculature (e.g., retinopathy of prematurity or incontinentia pigmenti) or damage to mature retinal vessels (e.g., diabetic retinopathy, retinal vein occlusion, or sickle cell retinopathy) leads to retinal ischemia (1). Although diverse (and poorly understood) etiologies may lead to insufficient perfusion of the retina, all lead to a common sequelae: the formation of abnormal leaky blood vessels that can manifest clinically with the accumulation of fluid in the inner retina [i.e., macular edema (ME)] and often, a profound loss of vision (2). Indeed, ME in patients with ischemia-induced retinopathies remains the leading cause of vision loss in the working age population in the developed world (3).The concept that ischemic retinopathies are driven by ischemia-induced angiogenic factors was proposed over half a century ago (4). A single transcriptional activator, hypoxia-inducible factor-1 (HIF-1), has recently emerged as the master regulator of these angiogenic mediators. HIF-1 is a heterodimeric protein composed of an exquisitely oxygen-sensitive α-subunit and a ubiquitous β-subunit. Under hypoxic conditions, degradation of the oxygensensitive HIF-1α subunit is reduced, whereas its trans...

show abstract

Section: Discussionmentioning

confidence: 99%

Hypoxic retinal Müller cells promote vascular permeability by HIF-1–dependent up-regulation of angiopoietin-like 4

Xin¹,

Rodrigues²,

Umapathi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

125

113

View full text Add to dashboard Cite

show abstract

“…The importance of evaluating the invasive front has been reported in several gastrointestinal malignancies [28][29][30][31]. In the present study, we examined RacGAP1 expression at the invasive front in gastric cancer and observed the association of its expression with tumor progression and poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

et al. 2014

View full text Add to dashboard Cite

Background Rac GTPase activating protein 1 (RacGAP1) plays a regulatory role in cell growth, transformation and metastasis. The aim of this study was to clarify the association between RacGAP1 expression and clinical outcome in patients with gastric cancer. Methods A total of 232 gastric cancer patients in our institute who underwent surgery without preoperative treatments were enrolled in this study. We investigated RacGAP1 expression using immunohistochemistry (IHC) and evaluated IHC scores calculated by the percentage of positive cells and intensity and its expression at the invasive front. RACGAP1 expression was also assessed. Results RacGAP1 expression was observed in the nuclei of gastric cancer cells. Evaluation by IHC score showed no significant correlations with clinicopathological variables except for histological differentiation. In transcriptional analyses, RACGAP1 expression was elevated in diffuse type gastric cancer than intestinal type without a significant difference. We observed significant correlations of Rac-GAP1 protein expression at the invasive front with older age, tumor size, lymph node metastasis, lymphatic invasion, vascular invasion and advanced stage. Patients with RacGAP1 protein expression at the invasive front had significantly poorer prognosis than those without it (P \ 0.0001). In multivariate analysis, lymph node metastasis, distant metastasis and positive RacGAP1 expression at the invasive front were independent prognostic factors (lymph node metastasis: P = 0.0106; distant metastasis: P = 0.0012; RacGAP1: P = 0.0011). Conclusions RacGAP1 expression at the invasive front in gastric cancer was significantly correlated with factors reflecting tumor progression and poor prognosis. Our data suggest that RacGAP1 might play important roles in the progression of gastric cancer.

show abstract

“…Although several CRC studies have described the overexpression of MMP7 (Akishima-Fukasawa et al, 2011;Karamitopoulou et al, 2011;Nastase et al, 2011;Bujanda et al, 2013), a relationship between the MMP7-181A/G polymorphism and MMP7 overexpression in CRC patients remains to be verified.…”

Section: Association Analysismentioning

confidence: 97%

Association of MMP7-181A/G and MMP13-77A/G polymorphisms with colorectal cancer in a Mexican population

et al. 2014

View full text Add to dashboard Cite

ABSTRACT. Colorectal cancer (CRC) is characterized by enhanced expression and activity of several metalloproteinases (MMPs), including MMP13 and MMP7, which play an important role in tumor Genomic DNA samples were obtained from peripheral blood of 102 CRC patients and 125 blood donors who were included as the control group. Identification of polymorphisms was based on polymerase chain reaction-restriction fragment length polymorphism methodology. The association was estimated by the odds ratio (OR) test. The results showed that MMP7-181A/G and MMP13-77A/G variants were associated with CRC. For MMP7-181A/G, the AA (P = 0.02, OR = 3.38, 95% confidence interval (CI) = 1.16-9.84) and AG (P = 0.01, OR = 3.4, 95%CI = 1.17-9.83) genotypes were associated with an increased risk of CRC. For MMP13-77A/G, the AA and AG genotypes were associated with CRC (AA genotype: P = 0.04, OR = 3.2, 95%CI = 1.004-10.2; AG genotype: P = 0.01, OR = 4.08, 95%CI = 1.3-13.07). In conclusion, AA and AG genotype carriers for both polymorphisms are at a higher risk of developing CRC in this Mexican population.

show abstract

Histopathological predictors of regional lymph node metastasis at the invasive front in early colorectal cancer

Abstract: LN metastasis is regulated not only by the characteristics of cancer cells but also by microenvironmental factors of lymphatics and neutrophils, especially at the invasive front.

Cited by 55 publications

References 33 publications

Hypoxic retinal Müller cells promote vascular permeability by HIF-1–dependent up-regulation of angiopoietin-like 4

Hypoxic retinal Müller cells promote vascular permeability by HIF-1–dependent up-regulation of angiopoietin-like 4

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

Association of MMP7-181A/G and MMP13-77A/G polymorphisms with colorectal cancer in a Mexican population

Contact Info

Product

Resources

About