Early detection of gastrointestinal tumors improves patient survival. However, patients with these tumors are typically diagnosed at an advanced stage and have poor prognosis. The incidence and mortality of gastrointestinal cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers, are increasing worldwide. Novel diagnostic and therapeutic agents are required to improve patient survival and quality of life. The tumor microenvironment, which contains nontumor cells, signaling molecules such as growth factors and cytokines, and extracellular matrix proteins, plays a critical role in cancer cell proliferation, invasion, and metastasis. Transforming growth factor beta (TGF-β) signaling has dual roles in gastrointestinal tumor development and progression as both a tumor suppressor and tumor promoter. Here, we review the dynamic roles of TGF-β and its receptors in gastrointestinal tumors and provide evidence that targeting TGF-β signaling may be an effective therapeutic strategy.

Role of Estrogen Receptor-Positive/Negative Ratios in Regulating Breast Cancer: The alpha estrogen receptor (ERα) contributes to breast cancer progression and recent guidelines define ER positivity as 1 stained cells, and a few tumor tissues show no ERα expression at all or are at 100. Although ER and aromatase inhibitors are widely used to treat hormone receptor-positive (HR+) breast cancer, their effect on tumor activity at different ERα levels remains unclear. Therefore, we investigated the role of ERα+/ERα ratios in determining the ERα level. We used ERα stably transfected and wild-type MDA-MB-231 cells (MDA-MB-231^Trans−ER and MDA-MB-231^WT, respectively) as represented ER+ and ER cells, respectively, and MCF-7 cells were the positive control. MDA-MB-231^Trans−ER and MDA-MB-231^WT cells were mixed and cocultured at a ratio of 0, 20, 40, 70, and 100. Migration and invasion functions at different cell ratios were evaluated in vitro using the Transwell and scratch test. In a xenograft mouse model, the polarization of the tumor-associated (M2) macrophage and the expression of breast cancer gene 1 (BRCA1), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF)-α were measured. The results showed that the cell invasion and migration were significantly higher at 40 and 70 than they were at other ratios. Additionally, in vivo, the 70 ERα+/ERα-ratio was a critical indicator of cell activity and cytokine expression. The highest M2 level and expression of VEGR, TNF-α, BRCA1, and HER2 were shown at a ratio of 70. Moreover, the effects of ERα were not linear in breast cancer, indicating that the ERα status requires continuous monitoring during long-term endocrine treatment. These results indicate that during HR+ breast cancer treatment, the ERα+/ERα ratio may be a useful predictor and should be evaluated further.