Endothelial Cells Promote Colorectal Cancer Cell Survival by Activating the HER3-AKT Pathway in a Paracrine Fashion

Abstract

The regulation of colorectal cancer cell survival pathways remains to be elucidated. Previously, it was demonstrated that endothelial cells (EC) from the liver (liver parenchymal ECs or LPEC), the most common site of colorectal cancer metastases, secrete soluble factors in the conditioned medium (CM) that, in turn, increase the cancer stem cell phenotype in colorectal cancer cells. However, the paracrine effects of LPECs on other colorectal cancer cellular functions have not been investigated. Here, results showed that CM from LPECs increased cell growth and chemoresistance by activating AKT in colorectal cancer cells Using an unbiased receptor tyrosine kinase array, it was determined that human epidermal growth factor receptor 3 (ERBB3/HER3) was activated by CM from LPECs, and it mediated AKT activation, cell growth, and chemoresistance in colorectal cancer cells. Inhibition of HER3, either by an inhibitor AZD8931 or an antibody MM-121, blocked LPEC-induced HER3-AKT activation and cell survival in colorectal cancer cells. In addition, CM from LPECs increased tumor growth in a xenograft mouse model. Furthermore, inhibiting HER3 with AZD8931 significantly blocked tumor growth induced by EC CM. These results demonstrated a paracrine role of liver ECs in promoting cell growth and chemoresistance via activating HER3-AKT in colorectal cancer cells. This study suggested a potential of treating patients with metastatic colorectal cancer with HER3 antibodies/inhibitors that are currently being assessed in clinical trials for various cancer types.

Correlation of PRL3 expression with colorectal cancer progression

“…Studies have shown that PRL3 is associated with increased metastatic potential in several cancers including CRC 9,32,33 . PRL3 has been reported to activate PI3K/Akt signaling in different cancer cell models 18,34 and we have shown that PRL3 activates Akt through phosphorylation at serine 473 in colon cancer cells 4 . In the present study, we investigated the levels of PRL3 and phosphorylated Akt (S473) expressions in 26 paired human CRC primary tumor and liver metastatic tissue specimens using IHC methods.…”

Tumor microenvironment in gastric cancers

“…Endothelial and vascular blood vessel cells have a function beyond supplying nutrition to tumor tissues; they also act as cancer niche cells and create a cancer‐promoting environment 68 . For example, endothelial cells can stimulate and activate colorectal cancer stem cells in a paracrine or juxtacrine fashion by mediating Notch and Akt signaling 69,70 . Similarly, lymphatic endothelial cells can activate metastatic signatures 71,72 and immunoregulatory function 73 in gastric cancers via secretion of soluble factors, suggesting a paracrine tumor‐promoting function of endothelial cell lineage in gastric cancers.…”

Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer Cells by Inducing ERG Expression and Activating Akt/mTOR Signaling Pathway

“…Swarnali Acharyya et al first described that endothelial cells were involved in the development of chemoresistance of breast cancer via secretion of TNF-a (12). Increasing evidence has demonstrated that endothelial cells contribute to chemoresistance of cancer cells by secreting soluble factors in a paracrine fashion in lymphoma (13)(14)(15), glioblastoma (16,17), colorectal cancer (18,19), and other cancer types (20)(21)(22)(23). Results from these studies showed that secreted factors including exosomes from endothelial cells can activate "cancer-advancing" signaling pathways in cancer cells such as AKT, Wnt, NOTCH, and epithelial-mesenchymal transition pathways in favor of survival under chemotherapy.…”