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. 2010 Oct 15:8:101.
doi: 10.1186/1479-5876-8-101.

Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance

Chun-Wei Peng  1 , Xiu-Li Liu, Xiong Liu, Yan Li
Affiliations

Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance

Chun-Wei Peng et al. J Transl Med. .

Abstract

Background: Cancer invasion results from constant interactions between cancer cells and their microenvironment. Major components of the cancer microenvironment are stromal cells, infiltrating inflammatory cells, collagens, matrix metalloproteinases (MMP) and newly formed blood vessels. This study was to determine the roles of MMP-9, MMP-2, type IV collagen, infiltrating macrophages and tumor microvessels in gastric cancer (GC) invasion and their clinico-pathological significance.

Methods: Paraffin-embedded tissue sections from 37 GC patients were studied by Streptavidin-Peroxidase (SP) immunohistochemical technique to determine the levels of MMP-2, MMP-9, type IV collagen, macrophages infiltration and microvessel density (MVD). Different invasion patterns were delineated and their correlation with major clinico-pathological information was explored.

Results: MMP2 expression was higher in malignant gland compared to normal gland, especially nearby the basement membrane (BM). High densities of macrophages at the interface of cancer nests and stroma were found where BM integrity was destroyed. MMP2 expression was significantly increased in cases with recurrence and distant metastasis (P = 0.047 and 0.048, respectively). Infiltrating macrophages were correlated with serosa invasion (P = 0.011) and TNM stage (P = 0.001). MVD was higher in type IV collagen negative group compared to type IV collagen positive group (P = 0.026). MVD was related to infiltrating macrophages density (P = 0.040). Patients with negative MMP9 expression had better overall survival (OS) compared to those with positive MMP9 expression (Median OS 44.0 vs 13.5 mo, P = 0.036). Median OS was significantly longer in type IV collagen positive group than negative group (Median OS 25.5 vs 10.0 mo, P = 0.044). The cumulative OS rate was higher in low macrophages density group than in high macrophages density group (median OS 40.5 vs 13.0 mo, P = 0.056). Median OS was significantly longer in low MVD group than high MVD group (median OS 39.0 vs 8.5 mo, P = 0.001). The difference of disease-free survival (DFS) between low MVD group and high MVD group was not statistically significant (P = 0.260). Four typical patterns of cancer invasion were identified based on histological study of the cancer tissue, including Washing pattern, Ameba-like pattern, Spindle pattern and Linear pattern.

Conclusions: Proteolytic enzymes MMP9, MMP2 and macrophages in stroma contribute to GC progression by facilitating the angiogenesis. Cancer invasion patterns may help predict GC metastasis.

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Figures

Figure 1
Figure 1
Co-evolution of tumor cells and their microenvironment in cancer invasions. Both of tumor cells and their microenvironment are involved in cancer invasions. Invasion is the first observable step of cancer progression process that tumor cells cross the ECM barrier by proteolytic enzyme such as MMPs after acquiring invasive phenotypes (upper graph). In addition, tumor infiltrating macrophages and type IV collagen also play an important role in cancer invasion. In this process, cancer invasion networks capture "temporal evolution" and "spatial evolution" between tumor cells and microenvironment before mechanical macrotrack can be observed as stroma remodelling at the histological level (lower graph).
Figure 2
Figure 2
Positive staining of type IV collagen, MMP9, MMP2, macrophages, and microvessels. A. BM was revealed by type IV Collagen staining. B. MMP9 was secreted by GC cells and mesenchymal. C. MMP2 expression is higher in malignant gland versus normal gland, especially nearby the BM. D. Macrophages are mainly located in the margin of the tumor nest, and phagocytosis of cancer cells by macrophage was observed (red arrow). E. New microvessels were increased at the tumor front. And CD105 is highly expressed on proliferating endothelial cells of both the peri- and intratumoral blood vessels (red arrow). Magnifications: A, B, C, D, E, F: 100×; Inserts in lower left corner show the sub-cellular localization of immunostaining at higher magnification (400×). All tissues were adenocarcinoma of GC.
Figure 3
Figure 3
Kaplan-Meier analysis of overall survival (OS) and disease-free survival (DFS). The median OS and DFS for 37 patients overall and 29 patients without distant metastasis were 19.0 and 10.0 months, respectively (A, E). GC patients with negative MMP9 expression (-) displayed better OS (B, upper curve) compared to those with positive MMP9 expression (B, lower curve) (P = 0.036, Log-rank test). Type IV collagen is a protective factor for GC patients (C, P = 0.044, Log-rank test). High MVD may predict poor OS (D, P = 0.001, Log-rank test). Low density of infiltrating Macrophages showed a tendency towards favorable DFS. Patients in low density of infiltrating macrophages group expression displayed improve DFS (F, upper curve) compared to patients with high density group expression (F, lower curve) (P = 0.013, Log-rank test).
Figure 4
Figure 4
Patterns of GC invasion. (A, B) Washing pattern: cancer cells encroach extracllular matrix everywhere, like wave breaking the dike on the beach. (C) Ameba-like pattern: after breaking the collagen, cancer cells invade ECM along the interspace of collagen on both sides to form an Ameba-like ulcer. (D) Spindle pattern: cancer cells proliferate with polarity, and the collagen at the tumor-invasion front is hydrolyzed to overcome the ECM barrier, forming a potential invasive tunnel. (E, F) Linear pattern: cancer cells digest the ECM main along a line. (G, H) Type IV collagen was abruptly degraded at a point, several cells were migrating (G). Though type IV collagen was not broken, degradation was obvious. Magnifications: A: 200×, B-H: 400×. Red arrows present the trend of invasion. Black arrows indicate the breaking points of IV collagen by hydrolysis. All tissues were adenocarcinoma of GC.
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