Lysyl oxidase-like 2 (LOXL2) from stromal fibroblasts stimulates the progression of gastric cancer

Kasashima, Hiroaki; Yashiro, Masakazu; Kinoshita, Haruhito; Fukuoka, Tatsunari; Morisaki, Tamami; Masuda, Go; Sakurai, Katsunobu; Kubo, Naoshi; Ohira, Masaichi; Hirakawa, Kosei

doi:10.1016/j.canlet.2014.08.014

Cited by 72 publications

(79 citation statements)

References 27 publications

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“…We can only speculate that the properties of CAFs, which can promote cancer progression, depend on a constant cross talk with cancer cells, and thus CAFs may not be formed in the early phase of the disease. In fact, several specific biomarkers determining the characteristics of CAFs, such as Twist-related protein 1, tumor endothelial marker 1, and lysyl oxidase like 2, are frequently overexpressed in the fibroblasts of GCs with higher T categories [22,30,31], supporting the notion that ''fully activated CAFs'' may be completed in an advanced stage of disease, with an increased number of CAFs, as shown by our data.…”

Section: Discussionsupporting

confidence: 67%

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

et al. 2016

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Objective The aim of this study was to evaluate the prognostic significance of the intratumor stromal proportion in gastric signet ring cell (SRC) carcinomas. Background Cancer stroma, as exemplified by cancer-associated fibroblasts (CAFs), plays critical roles in cancer proliferation, invasion, and metastasis. Methods One hundred seventy-five SRC carcinoma cases were classified according to the intratumor desmoplastic stromal proportion to then analyze the clinicopathologic characteristics of stroma-rich cases. We also investigated the impact of CAFs on the migration as well as on the phenotypic changes of gastric SRC carcinomas in vitro.Furthermore, we performed RNA sequencing of a pair of CAFs and normal-tissue-associated fibroblasts. Results Stroma-rich SRC carcinomas (64 of 175 cases, 36.5%) were associated with female patients (P = 0.045), large tumor size (P = 0.007), higher T category (P \ 0.001), and the presence of perineural invasion (P = 0.018). Patients with stroma-rich SRC carcinomas had a significantly shorter disease-free survival (P \ 0.001) and overall survival (P \ 0.001). However, in a subgroup analysis, the prognostic significance of the stromal proportion correlated only with patients with T3/4 disease. From multivariate analysis, the high stromal proportion is an independent prognostic factor to predict worse disease-free survival (hazard ratio 2.288; P = 0.001) and overall survival (hazard ratio 2.503; P = 0.001). We found that CAFs enhanced the migratory abilities of cancer cells through the epithelial-mesenchymal transition, and RNA sequencing results confirmed these findings. Conclusions The intratumor stromal proportion could be a useful prognostic biomarker and a potential therapeutic target in gastric SRC carcinomas.

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Section: Discussionsupporting

confidence: 67%

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

et al. 2016

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“…The methods used for the immunohistochemical determination are described in the kit manufacturer's instructions, as previously reported [14]. LOX expression was evaluated by the intensity of staining and the percentage of stained cancer cells at the invading tumor front: intensity was given a score ranging from 0 to 2 (0 = no intensity, 1 = weak to moderate intensity, 2 = intense intensity), and the percentage of immunopositive cells was given a score ranging from 0 to 4 (0 = 0 %, 1 = 1-30 %, 2 = 31-60 %, 3 = 61-80 %, 4 = 81-100 %).…”

Section: Immunohistochemical Determination Of Loxmentioning

confidence: 99%

“…LOX and its family members, LOX-like 1-4, oxidize lysine residues in collagens and elastin [10], which results in covalent cross-linking and stabilization of these extracellular matrix structural components, conferring on collagen and elastic fibers much of their tensile strength [11]. LOX families are involved in a variety of pathological processes related to connective tissue [12,13], including cancer progression and metastasis [11,14]. Involvement of the LOX family is widely accepted as a poor prognostic factor for patients with cancer [15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

et al. 2015

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Purpose It has been reported that lysyl oxidase (LOX) is a hypoxia-responsive factor and is associated with the malignant progression of carcinoma. The aim of this study was to clarify the relationship between the epithelialmesenchymal transition (EMT) and LOX in gastric cancer cells under hypoxia. Methods Two gastric cancer cell lines, OCUM-2MD3 and OCUM-12, were used in an in vitro study. The effect of LOX small interfering RNA (siRNA) on the EMT and motility of gastric cancer cells under hypoxic condition was analyzed by reverse transcription PCR, Western blot, a wound-healing assay, and an invasion assay. Correlations between LOX expression and the clinicopathological features of 544 patients with gastric carcinoma were examined immunohistochemically.Results Hypoxic conditions increased the number of polygonal or spindle-shaped cells resulting from EMT in gastric cancer cells. The EMT of cancer cells induced by hypoxia was inhibited by treatment with LOX siRNA. The number of migrating and invading gastric cancer cells in hypoxia was significantly decreased by LOX knockdown. LOX siRNA significantly increased the E-cadherin level and decreased the vimentin level of gastric cancer cells. LOX expression was significantly associated with invasion depth, tumor differentiation, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal metastasis. Multivariable analysis revealed that LOX was an independent parameter for overall survival. Conclusion LOX affects the EMT of gastric cancer cells in hypoxic conditions. LOX expression is a useful prognostic factor for patients with gastric cancer.

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“…201,245 Alternatively, LOXL2 may be secreted by local CAFs to influence ECM composition, and this has been shown in gastric cancer cell lines to be associated with increased aggressiveness. 251 In addition, increased LOXL2 expression in CAFs is associated with reduced OS and increased recurrence in colon cancer patients. 247 The…”

Section: Discussionmentioning

confidence: 99%

“…250 LOXL2 may be secreted by stromal cancer-associated fibroblasts or tumour cells. 247,251 LOXL2 secreted by tumour cells has also been shown to activate stromal fibroblasts and cause local desmoplasia (fibrosis), possibly via FAK (focal adhesion kinase) signalling. 199 Increased expression of LOXL2 in stromal fibroblasts has also been shown to be associated with aggressiveness in gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

Epidemiological and molecular features of cutaneous squamous cell carcinoma with perineural spread

Warren¹

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Lysyl oxidase-like 2 (LOXL2) from stromal fibroblasts stimulates the progression of gastric cancer

Cited by 72 publications

References 27 publications

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

Epidemiological and molecular features of cutaneous squamous cell carcinoma with perineural spread

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