Masakazu Toi

Although overexpression of human epidermal growth factor receptor 2 (HER2) protein, amplification of the gene or both are associated with poor prognosis in breast cancer, trastuzumab has clearly provided clinical benefits in metastatic breast cancer, adjuvant treatment settings and primary systemic therapy. However, even in those HER2 overexpressors, the majority of patients who achieve an initial response generally acquire resistance within 1 year. Therefore, it is critical to elucidate the mechanism of resistance and to search for better combination treatments with chemotherapeutic agents or other novel modalities. Here, we discuss both clinical and preclinical data regarding these issues.

We examined the expression of sVEGFR1 in colorectal cancer tissue and corresponding normal colorectal mucosa to assess the clinical significance of sVEGFR1 in colorectal cancer. We also assessed the relationship between sVEGFR1 levels and various clinicopathologic factors and prognoses. sVEGFR1 and VEGF levels were measured in fresh‐frozen tumor extracts from 84 primary colorectal cancer tissues and 27 corresponding normal mucosa using ELISA. Mean of sVEGFR1 levels were 3.17 ng/mg protein. sVEGFR1 levels increased significantly in cancer tissue compared with normal mucosa. Although VEGF levels increased in cancer tissues, the ratio of sVEGFR1/VEGF in cancer tissue was significantly lower than that in normal tissue. No significant correlation between sVEGFR1 or VEGF levels and any clinicopathologic parameter was found. Overexpression of sVEGFR1 was significantly associated with a favorable prognosis. Based on sVEGFR1 levels in colorectal cancer without distant metastases, patients with higher sVEGFR1 levels (≥1.5 ng/mg protein) demonstrated significant longer recurrence‐free survival than patients with lower sVEGFR1 levels (P = 0.0017). Multivariate analysis showed that the sVEGFR1 levels in cancer tissue were an independent prognostic indicator of disease progression. sVEGFR1 expression was significantly elevated in colorectal cancer tissue compared with normal mucosa and the intratumoral balance between sVEGFR1 and VEGF was significantly different between tumor tissue and normal controls. Furthermore, sVEGFR1 levels showed a significant prognostic value. Further studies concerning the biologic and therapeutic significance of sVEGFR1 in colorectal cancer are warranted. (Cancer Sci 2007; 98: 405–410)

Macrophage migration inhibitory factor (MIF) is known to exert pleiotropic functions including inhibition of macrophage migration, anchoring, and counteraction of the anti‐inflammatory and immunosuppressive activity of glucocorticoids. Ninety‐three primary breast cancer tissues and 64 sera of primary breast cancer patients were analyzed for the expression of MIF. The clinico‐pathological significance of MIF expression was evaluated. It was found that MIF was frequently over‐expressed in primary breast cancer tissues. RT‐PCR and western blotting analysis confirmed that wild‐type MIF is expressed, and immunohistochemical analysis showed that MIF expression was localized at tumor cells as well as stromal cells, including tumor‐associated macrophages. Intra‐tumoral MIF protein concentrations detected by enzyme‐linked immunosorbent assay (ELISA) varied with a median value of 1821 ng/mg protein (range: 8–8126 ng/mg protein), and correlated inversely with nodal involvement (P=0.039). No significant correlation was observed with other clinico‐pathological factors including tumor size, menopausal status and hormone receptors. The circulating level of MIF protein ranged up to 105.7 ng/ml (median: 17.3 ng/ml), and it was also found to correlate inversely with the number of involved nodes (P=0.02). A comparative study with other soluble inflammatory mediators showed that intratumoral levels of MIF were significantly associated with those of interleukin‐1β, suggesting that interactions between tumor cells and tumor‐associated macrophages play an important role in the up‐regulation of MIF. The multifunctional inflammatory/immune mediator MIF was frequently expressed in primary breast cancer, and its expression level was inversely associated with nodal spread. Thus, MIF seems to play a role in tumor‐stroma interactions of primary breast cancers, particularly those with a phenotype of node‐negative or minimal nodal spread.

BACKGROUND Macrophages often infiltrate into solid tumor tissues. Tumor‐associated macrophages (TAMs) are known to play a crucial role in tumor progression. Monocyte chemoattractant protein‐1 (MCP‐1) is one of the major chemokines capable of inducing chemotactic migration of monocytes. METHODS With the objective of investigating the clinical significance of MCP‐1, the authors analyzed the expression of MCP‐1 and of some other molecules by immunohistochemistry in 230 samples of primary breast carcinoma tissue. MCP‐1 staining was performed using an anti‐MCP‐1 monoclonal antibody, and it was assessed by grading the percentage of stained cells. RESULTS It was found that 117 breast tumor specimens (51%) had intensive staining in tumor cells. The expression of MCP‐1 in tumor cells had a significant correlation with the expression of thymidine phosphorylase and membrane type 1‐matrix metalloproteinase. In addition, MCP‐1 expression tended to be associated with the accumulation of TAMs, which were counted by CD68 staining, and with microvessel density. MCP‐1 expression in TAMs was correlated significantly with the histologic vessel invasion of tumor cells. CONCLUSIONS The results of this study suggest that MCP‐1 may play key roles in macrophage recruitment, in the expression of angiogenic factors, and in the activation of matrix metalloproteinases in patients with breast carcinoma. Cancer 2001;92:1085–91. © 2001 American Cancer Society.

Expression of matrix metalloproteinases (MMPs) plays an essential role in tumor metastasis and invasion through the degradation of extracellular matrix (ECM). MT1‐MMP (membrane type 1 matrix metalloproteinase), a membrane‐type MMP, is responsible for the activation of MMP2. In this study the significance of MT1‐MMP expression in human breast tumors was investigated by immunocytochemical assay, and its correlation with clinicobiological features was analyzed. MT1‐MMP expression was detected in tumor cells and/or stromal cells, and there was a strong correlation between the expressions of MT1‐MMP in the two cell types. Out of 183 primary tumors, 103 (56.2%) showed positive staining of MT1‐MMP in tumor cells. MT1‐MMP expression showed no significant correlation with any of the clinicobiological parameters examined, including hormone receptor status and angiogenesis. In postoperative survival analysis, MT1‐MMP expression itself was not a significant prognostic factor. However, in the particular subgroup with the accumulation of thymidine phosphorylase (TP)‐positive stromal cells, which have been activated by various stimuli, such as cytokines and hypoxia, MT1‐MMP expression had a significant prognostic value. These data suggested that MT1‐MMP might function cooperatively with tumor‐associated stromal cells for the progression of breast cancer.