The role of epidermal growth factor receptor in cancer metastasis and microenvironment

Abstract

Despite significant improvements in diagnosis, surgical techniques, and advancements in general patient care, the majority of deaths from cancer are caused by the metastases. There is an urgent need for an improved understanding of the cellular and molecular factors that promote cancer metastasis. The process of cancer metastasis depends on multiple interactions between cancer cells and host cells. Studies investigating the TGF α-EGFR signaling pathways that promote the growth and spread of cancer cells. Moreover, the signaling activates not only tumor cells, but also tumor-associated endothelial cells. TGF α-EGFR signaling in colon cancer cells creates a microenvironment that is conducive for metastasis, providing a rationale for efforts to inhibit EGFR signaling in TGF α-positive cancers. In this review, we describe the recent advances in our understanding of the molecular basis of cancer metastasis.

Figure 1

Immunohistochemical analyses of expression of TGFα, EGFR, and phosphorylated EGFR on tumor cells and tumor-associated endothelial cells in orthotopically implanted colon tumors. (a) TGFα expression in the tumor cells. (b) EGFR was present on tumor cells (green) and was also detected on the tumor-associated vasculature (yellow). (c) Expression of phosphorylated EGFR was localized to both tumor cells (green) and the supporting vascular network (yellow). Scale bars = 100 μm [50].

Figure 2

Immunohistochemical analyses of expression of VEGFA, IL-8, MMP-2, and MMP-9 in orthotopically implanted colon tumors. The parental colon cancer cell line originates from a primary human colon carcinoma. The clones were expanded, and the resulting populations were screened for production of TGFα. The microenvironment of selected high level TGFα tumors is enriched in VEGFA, IL-8, MMP-2, and MMP-9. Expression of the angiogenic proteins in tumors that do not express TGFα is significantly attenuated. Scale bars = 100 μm [50].

Figure 3

Immunofluorescent staining of LYVE-1, F4/80, and VEGFC in human colon carcinoma cells expressing different levels of TGFα. Lymphatic vessels are labeled with LYVE-1 (green) and macrophage cells with F4/80 (red). The number of tumor-associated lymphatic vessels was greatest in selected high-level TGFα tumors and fewest in tumors that do not express TGFα. Tumor recruitment of macrophages was also fewest in tumors that do not express TGFα. Macrophage cells localized to selected high level TGFα tumors also expressed LYVE-1. The macrophage population recruited to TGFα-expressing tumors also produced abundant levels of the lymphatic endothelial cell growth factor VEGFC. Scale bars = 100 μm [50].

Figure 4

Mean density of LYVE-1 on orthotopic colon tumors expressing different levels of EGFR. The SW620CE2 is human colon cancer cell line. SW620 cells were injected into the cecal wall of nude mice. Three months after the injection, cecal tumors were harvested. Cells were established in culture. Primary cultures were passaged in vitro two or three times, and then, cells were injected into the cecum of another set of nude mice. The selection cycle was repeated two times to yield cell lines designated SW620CE2. SW620CE2 did not produce detectable levels of EGFR. SW620CE2/EGFR was established from SW620CE2 which was transfected sense EGFR plasmids. Cells (5 × 10⁵) in 50 μL of Hanks' buffered saline solution were injected into the cecal wall of nude mice. The number of lymphatic vessels in SW620CE2/EGFR tumors was fourfold higher than that observed in SW620CE2 tumors [56].