Interaction Between Stromal Fibroblasts and Colorectal Cancer Cells in the Expression of Vascular Endothelial Growth Factor

Koshida, Yoshitomo; Kuranami, Masaru; Watanabe, Masahiko

doi:10.1016/j.jss.2006.02.025

Cited by 22 publications

(14 citation statements)

References 27 publications

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“…Previously, up-regulation of VEGF expression in human colonic fibroblasts was detected when co-cultured with colorectal cancer cells. 31 However, our current study indicated that co-cultivation with TAFs failed to enhance the expression of VEGF-C and -D in tumor cells. The in vitro reconstitution experiment may therefore imply that cancer cells maintain favorable biological conditions for lymphangiogenesis through HA-induced TAF recruitment rather than via the up-regulation of lymphangiogenic factors.…”

Section: Discussioncontrasting

confidence: 63%

Significance of Tumor-Associated Stroma in Promotion of Intratumoral Lymphangiogenesis

Koyama

Kobayashi

Harada

et al. 2008

The American Journal of Pathology

115

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Stromal cells, together with extracellular matrix components, provide a tumor microenvironment that is pivotal for cancer cell growth and progression. In our previous study using a conditional transgenic mouse model of breast cancer, the overproduction of hyaluronan, a major extracellular constituent, accelerated tumor angiogenesis through stromal cell recruitment. This finding led us to investigate the role of hyaluronan in the lymphatic vessel system. Here, we have found that microenvironmental hyaluronan promoted tumor lymphangiogenesis concurrently with the formation of stromal structures. Additionally, lymphatic vessels frequently penetrated and accumulated into stromal compartments, and up-regulation of vascular endothelial growth factor-C and -D was detected at tumor-stromal interfaces. To assess the contribution of stromal cells to lymphangiogenesis in vivo, we established tumor-associated fibroblasts from hyaluronan-overproducing mammary tumors and implanted them together with carcinoma cells from control tumors or MCF-7 human breast carcinoma cells in nude mice. Carcinoma cells grew rapidly in association with marked stromal reactions and lymphangiogenesis. Without the stromal cells, however, the tumors developed slowly with less stroma and lymphatic vessels. These findings underline the significance of tumor-associated stroma in the promotion of intratumoral lymphangiogenesis and suggest a pivotal role for the hyaluronan-rich tumor microenvironment.

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Section: Discussioncontrasting

confidence: 63%

Significance of Tumor-Associated Stroma in Promotion of Intratumoral Lymphangiogenesis

Koyama

Kobayashi

Harada

et al. 2008

The American Journal of Pathology

115

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“…Similarly, extensive characterization of the tumor-associated stroma, predominantly comprising of cancer-associated fibroblasts and extracellular matrix, has identified pertinent roles in facilitating tumor growth and invasion (13), angiogenesis (14,15) and energy homeostasis (16). Of interest, however, it has been reported, again using routine pathologic specimens, that a high stroma to tumor ratio is associated with the presence of adverse pathologic characteristics (17).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a Tumor Microenvironment–Based Prognostic Score in Primary Operable Colorectal Cancer

Park

McMillan

Powell

et al. 2015

Clinical Cancer Research

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Purpose: The tumor microenvironment is recognized as an important determinant of progression and outcome in colorectal cancer. The aim of the present study was to evaluate a novel tumor microenvironment-based prognostic score, based on histopathologic assessment of the tumor inflammatory cell infiltrate and tumor stroma, in patients with primary operable colorectal cancer.Experimental Design: Using routine pathologic sections, the tumor inflammatory cell infiltrate and stroma were assessed using Klintrup-M€ akinen (KM) grade and tumor stroma percentage (TSP), respectively, in 307 patients who had undergone elective resection for stage I-III colorectal cancer. The clinical utility of a cumulative score based on these characteristics was examined.Results: On univariate analysis, both weak KM grade and high TSP were associated with reduced survival (HR, 2.42; P ¼ 0.001 and HR, 2.05; P ¼ 0.001, respectively). A cumulative score based on these characteristics, the Glasgow Microenvironment Score (GMS), was associated with survival (HR, 1.93; 95% confidence interval, 1.36-2.73; P < 0.001), independent of TNM stage and venous invasion (both P < 0.05). GMS stratified patients in to three prognostic groups: strong KM (GMS ¼ 0), weak KM/ low TSP (GMS ¼ 1), and weak KM/high TSP (GMS ¼ 2), with 5-year survival of 89%, 75%, and 51%, respectively (P < 0.001). Furthermore, GMS in combination with node involvement, venous invasion, and mismatch repair status further stratified 5-year survival (92% to 37%, 93% to 27%, and 100% to 37%, respectively).Conclusions: The present study further confirms the clinical utility of assessment of the tumor microenvironment in colorectal cancer and introduces a simple, routinely available prognostic score for the risk stratification of patients with primary operable colorectal cancer.

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“…The fibroblasts of the tumour associated stroma can affect tumour development by secreting soluble factors such as vascular endothelial growth factor (VEGF) [26] and matrix metalloproteinases (MMP:s) [27]. ILK contributes to tumour progression by increasing the expression of VEGF via the activation of PKB/Akt and HIF-1α, thereby stimulating angiogenesis [28].…”

Section: Discussionmentioning

confidence: 99%

Impact of PINCH expression on survival in colorectal cancer patients

et al. 2011

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BackgroundThe adaptor protein PINCH is overexpressed in the stroma of several types of cancer, and is an independent prognostic marker in colorectal cancer. In this study we further investigate the relationship of PINCH and survival regarding the response to chemotherapy in colorectal cancer.ResultsParaffin-embedded tissue sections from 251 primary adenocarcinomas, 149 samples of adjacent normal mucosa, 57 samples of distant normal mucosa and 75 lymph node metastases were used for immunohistochemical staining. Stromal staining for PINCH increased from normal mucosa to primary tumour to metastasis. Strong staining in adjacent normal mucosa was related to worse survival independently of sex, age, tumour location, differentiation and stage (p = 0.044, HR, 1.60, 95% CI, 1.01-2.52). PINCH staining at the invasive margin tended to be related to survival (p = 0.051). In poorly differentiated tumours PINCH staining at the invasive margin was related to survival independently of sex, age and stage (p = 0.013, HR, 1.90, 95% CI, 1.14-3.16), while in better differentiated tumours it was not. In patients with weak staining, adjuvant chemotherapy was related to survival (p = 0.010, 0.013 and 0.013 in entire tumour area, invasive margin and inner tumour area, respectively), but not in patients with strong staining. However, in the multivariate analysis no such relationship was seen.ConclusionsPINCH staining in normal adjacent mucosa was related to survival. Further, PINCH staining at the tumour invasive margin was related to survival in poorly differentiated tumours but not in better differentiated tumours, indicating that the impact of PINCH on prognosis was dependent on differentiation status.

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Interaction Between Stromal Fibroblasts and Colorectal Cancer Cells in the Expression of Vascular Endothelial Growth Factor

Cited by 22 publications

References 27 publications

Significance of Tumor-Associated Stroma in Promotion of Intratumoral Lymphangiogenesis

Significance of Tumor-Associated Stroma in Promotion of Intratumoral Lymphangiogenesis

Evaluation of a Tumor Microenvironment–Based Prognostic Score in Primary Operable Colorectal Cancer

Impact of PINCH expression on survival in colorectal cancer patients

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