Abstract
Simple SummaryExcessive angiogenesis is a distinct feature of colorectal cancer (CRC) and plays a pivotal role in tumor development and metastasis. Therefore, it is essential to clarify the underlying mechanism of angiogenesis. In this study, we found that the level of proline-, glutamic acid, and leucine-rich protein 1 (PELP1) was positively correlated with microvessel density (MVD). In vitro and in vivo assays further showed PELP1 regulated angiogenesis via the Signal transducer and activator of transcription 3 (STAT3)/Vascular endothelial growth factor (VEGFA). Notably, we found that inhibition of PELP1 enhanced the efficacy of chemotherapy due to vascular normalization. Thus, targeting of PELP1 may be a potentially therapeutic strategy for CRC.Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its involvement in angiogenesis is unknown. In this study, PELP1 was found to be abnormally upregulated and highly coincidental with increased MVD in CRC. Further, treatment with conditioned medium (CM) from PELP1 knockdown CRC cells remarkably arrested the function of human umbilical vein endothelial cells (HUVECs) compared to those treated with CM from wildtype cells. Mechanistically, the STAT3/VEGFA axis was found to mediate PELP1-induced angiogenetic phenotypes of HUVECs. Moreover, suppression of PELP1 reduced tumor growth and angiogenesis in vivo accompanied by inactivation of STAT3/VEGFA pathway. Notably, in vivo, PELP1 suppression could enhance the efficacy of chemotherapy, which is caused by the normalization of vessels. Collectively, our findings provide a preclinical proof of concept that targeting PELP1 to decrease STAT3/VEGFA-mediated angiogenesis and improve responses to chemotherapy due to normalization of vessels. Given the newly defined contribution to angiogenesis of PELP1, targeting PELP1 may be a potentially ideal therapeutic strategy for CRC as well as other solid tumors.
Highlights
Angiogenesis plays a vital role in the progression and metastasis of solid tumors, including colorectal cancer (CRC) [1,2]
The present study revealed that the high expression of PELP1 is closely related with angiogenesis in CRC.We proved that PELP1 promotes tumor angiogenesis by activating the STAT3 pathway
It is worth noting that suppression of PELP1 reduces VEGF expression and secretion, and enhances the efficacy of tumor chemotherapy via vascular normalization, which provides a novel target for anti-angiogenesis in CRC
Summary
Angiogenesis plays a vital role in the progression and metastasis of solid tumors, including colorectal cancer (CRC) [1,2]. The levels of angiogenesis are in a static and stable state due to the balance between pro-angiogenic factors and anti-angiogenic factors [4] In cancer, this dynamic balance is disrupted, and the tumor microenvironment (TME) secretes excessive pro-angiogenic factors to promote angiogenesis and lead to vessel abnormalization [5]. The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and placental growth factor, of which VEGFA is the most important and main component of the VEGF family, and VEGFA has been shown to be associated with the poor prognosis of a variety of solid tumors, including CRC [3]. A variety of anti-angiogenic drugs targeting VEGF and its receptors have been developed and applied to the clinical treatment of tumors [7]. Bevacizumab, which targets VEGF, has been used as a first-line therapy for CRC patients, and has achieved a satisfactory effect [8]
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