Abstract
BackgroundCancer 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.MethodsParaffin-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.ResultsMMP2 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.ConclusionsProteolytic enzymes MMP9, MMP2 and macrophages in stroma contribute to GC progression by facilitating the angiogenesis. Cancer invasion patterns may help predict GC metastasis.
Highlights
Cancer invasion results from constant interactions between cancer cells and their microenvironment
Instead of investigating a single component of cancer matrix, this study focused on the whole tumor microenvironment related to gastric cancer (GC) invasion, by evaluating tissue destructive proteolytic enzymes MMP9 and MMP2, tissue barriers against invasion like type IV collagen, tumor infiltrating macrophages, and tumor angiogenesis, all of which are essential components of tumor stroma and involved in the process of invasion (Figure 1.)
MMP2 expression was higher in malignant gland compared to normal gland, especially nearby the basement membrane (BM) (Figure 2C)
Summary
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. A seminal event in cancer progression is the ability of cancer cells to mobilize the necessary machinery to break surrounding extracellular matrix (ECM) barriers while orchestrating a host stroma response that supports tissue-invasive and metastatic processes [6]. The cancer cell and stroma both modulate the process of invasion by remodeling the ECM with tumor-associated proteases such as matrix metalloproteinase (MMPs), which subsequently breakdown proteins of the ECM such as collagens and release the cryptic information [8,9]. The process of pericellular proteolysis leads to ECM degradation and realignment during cell movement and integrate it into established steps of cell migration [11]
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