The tumor microenvironment (TME) is a hypoxic, acidic, and immune/inflammatory cell-enriched milieu that plays crucial roles in tumor development, growth, progression, and therapy resistance. Targeting TME is an attractive strategy for the treatment of solid tumors. Conventional cancer chemotherapies are mostly designed to directly kill cancer cells, and the effectiveness is always compromised by their penetration and accessibility to cancer cells. Small-molecule inhibitors, which exhibit good penetration and accessibility, are widely studied, and many of them have been successfully applied in clinics for cancer treatment. As TME is more penetrable and accessible than tumor cells, a lot of efforts have recently been made to generate small-molecule inhibitors that specifically target TME or the components of TME or develop special drug-delivery systems that release the cytotoxic drugs specifically in TME. In this review, we briefly summarize the recent advances of small-molecule inhibitors that target TME for the tumor treatment.

Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2–YES1–ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2–YES1–ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC.

Yes‐associated protein (YAP) is a transcriptional coactivator that promotes cell proliferation, stem cell maintenance and tissue homeostasis. The YAP activity is primarily regulated through an inhibitory phosphorylation by the serine/threonine kinases of Hippo pathway. Here, we show that receptor tyrosine kinase (RTK) erythropoietin‐producing hepatocellular receptor A2 (EphA2) interacts with and phosphorylates YAP protein, leading to stabilization, nuclear translocation and activation of YAP in gastric cancer (GC) cells. EphA2 induces chemotherapy‐resistance by increasing YAP stability and nuclear YAP protein. Knockdown of YAP blocks EphA2‐induced tumor growth in GC xenograft mouse models. Importantly, the coactivation of EphA2 and YAP is manifested in clinical human GC, and is related to GC recurrence. Thus, our results establish a novel EphA2‐to‐YAP pathway that drives GC growth, progression and therapy‐resistance, targeting this pathway would be an efficient way for the treatment of GC, particularly chemotherapy‐resistant GC.

This SEER-based study aimed to explore and analyze the relationship of metastasis of liver, lung and bone of GIST patients and their prognosis.

The mevalonate pathway is known for the synthesis of cholesterol, but recent studies have reported that it also controls Hippo signaling, which is critical for the regulation of organ size and tumorigenesis. Here, we discover that the suppression of the mevalonate pathway inhibits the growth and proliferation of colon cancer cell lines. The results of transcriptomic and proteomic assays suggested that the mevalonate pathway controls multiple signaling pathways relevant to cell proliferation, and the results were further confirmed using western blot, PCR, and immunofluorescence assays. As cell proliferation is an energy-consuming process, we postulate that the mevalonate pathway may also control nutrient uptake to coordinate the processes of energy supply and cell proliferation. Here, we found that lovastatin, a mevalonate pathway inhibitor, suppresses glucose and amino acid uptake and lactate acid production. More importantly, mevalonic acid itself is sufficient to promote glucose uptake by colon cancer cells. In addition, we found that colon cancer tissues displayed a higher expression of mevalonate pathway enzymes, which may promote cell growth and stimulate energy uptake. Together, our findings establish the mevalonate pathway as a critical regulator in coordinating energy input and cell proliferation.

Through bioinformatics analysis, a novel lncRNA, LINC00460, was implicated in the development of multiple cancers. However, the precise expression pattern, clinical significance and biological function of LINC00460 in colorectal cancer (CRC) remain unknown. Network databases were used to investigate the correlation between LINC00460 and CRC. In situ hybridization was performed to verify the precise expression pattern and clinical significance of LINC00460 in a CRC tissue microarray, which included 92 pairs of CRC and adjacent normal tissues. The effect of LINC00460 on proliferation was evaluated by MTT, colony formation assays and flow cytometry employing SW620 and HCT116 cell lines. Cell migration and matrigel invasion assays were performed to investigate whether LINC00460 is involved in the metastasis of CRC. The expression of LINC00460 was significantly upregulated in CRC tissues and cells, associated with early stage CRC and low disease-free survival. The downregulated of LINC00460 expression increased cell proliferation by regulating the cell cycles of SW620 and HCT116 cells. LINC00460 knockdown did not affect cell migration or invasion in vitro. These findings suggest that LINC00460 may be an interesting target for the development of CRC.