Dynamic Changes of Collagen Ⅳ During Cancer Invasion and Migration: Pulse Mode

Abstract

Cancer invasion and metastasis remain two root causes of mortality. This process involves alterations of tumor microenvironment, particularly the remodeling of extracellular matrix(ECM), characterized by collagen Ⅳ uncoiling, degradation, fragments deposition and cross-linking. This study was aimed to reveal the cancer invasion mode based on dynamic changes of collagen Ⅳ by novel quantum dots(QDs) imaging technology. Cancer tissues of hepatocellular carcinoma, gastric cancer, breast cancer and cervical carcinoma were collected and stained by traditional immunohistochemistry and novel QDs-based imaging technology. Several key molecules representing of cancer cells and tumor microenvironment were studied, including Ki67, representing of proliferation of cancer cells, macrophages, representing of monocytes infiltration and collagen Ⅳ, representing of tumor stroma remodeling during cancer invasion and migration. During cancer invasion and migration, collagen Ⅳ had structural and functional changes. In different cancer tissues, 4 types of collagen Ⅳ could be observed, consisting of linear, irregular, fragmented and disappeared. However, several common features were evident during the dynamic process of cancer progression. First, collagen Ⅳ at basement membrane increased, presenting an irregular sheath surrounding cancer nests; then, collagen Ⅳ was degraded to form invasion fronts at several sites accompanied with linear re-deposition of collagen Ⅳ and increased macrophages in ECM. Second, cancer cells escaped from large cancer nests to seed in ECM. And also the dynamic changes of collagen Ⅳ were accompanied with the recruitment of macrophages, together to regulate and affect biological behaviors of cancer cells. A series changes caused by dynamic changes of collagen Ⅳ provide a proper tumor microenvironment for cancer invasion and migration. In this dysfunctional tumor microenvironment, tumor mass becomes increasingly harder with tumor stroma stiffening causing high ECM stress. With cancer cells proliferation, tension becomes increasingly higher, till reaching a critical point, where large tumor nests "burst", releasing many tiny seeding nests and reducing the central ECM tension. The resulting seeding tumor nests repeat the same process of tumor mass growth →prominent central hypoxia→collagen Ⅳ cross-linking and deposition→ECM remodeling→ECM stress buildup→tumor nest bursts, leading to accelerated cancer progression in this rich "soil" of dysfunctional tumor microenvironment, presenting a "pulse mode".