Mechanisms of Tumor-Lymphatic Interactions in Invasive Breast and Prostate Carcinoma

Abstract

During the last few years, diverse studies have shown that tumors can actively interact with the lymphatic system and promote metastases development. In order to examine the molecular mechanisms involved in this interaction, we co-cultured tumor and lymphatic endothelial cells (LEC) and subsequently analyzed the molecular alterations of LECs. Therefore, LECs were co-cultivated with either a highly or weakly metastatic breast cancer cell line using contact (mixture) and non-contact (transwell) co-cultures. mRNA profiles from LECs were subsequently analyzed for genes specifically induced by highly metastatic tumor cells (“metastatic specific”). Among the up-regulated “metastatic specific” genes, we found candidates involved in cell cycle, cell adhesion and motility (BST2, E-selectin, and HMMR), cytokines (CCL7, CXCL6, CXCL1, and CSF2) and factors of the complement system (C1R, C3, and CFB). Among the down-regulated genes, we detected the hyaluronan receptor STAB2, angiogenic factor apelin receptor (APLNR), and the glycosylation enzyme MAN1A1. In an additional prostate cancer co-culture model, we could confirm a “metastatic specific” upregulation of E-selectin and CCL7 in LECs after interaction with the prostate cancer cell lines LNCAP (highly metastatic) and DU145 (weakly metastatic). These data allowed us to identify a set of genes regulated in LECs during in vitro communication with cancer cells, which might subsequently facilitate lymphatic metastasis.

Inside-Out of Complement in Cancer

“…These data were corroborated in vivo in an orthotopic mouse model of GBM where C5aR1 antagonism resulted in increased sensitivity of GBM to TMZ. Using in vitro co-cultures of breast and prostate cancer cells with lymphatic endothelial cells (LEC), Oliveira-Ferrer demonstrated tumor-dependent induction of C3, CFB and C1q secretion as well as that chemokine upregulation (CCL7, CXCL6, CXCL1) by the LECs promotes tumor metastasis ( 94 ).…”

Role of Exosomes in Prostate Cancer Metastasis

“…The lymphatic system is made up of the lymphatic vessels and lymphoid organs comprising of lymphocytes, lymph nodes, spleen, and tonsils. Over the years, a strong association has been found between tumor cells and tumor metastasis particularly in PCa [130,131]. An interesting route PCa-derived cells adapt during metastasis is through the lymphatic route where tumor cells intravasate into lymph nodes to get to their target sites thereby promoting aggressive phenotypes in PCa [131][132][133].…”

Roles of apelin/APJ system in cancer: Biomarker, predictor, and emerging therapeutic target

“…Apelin can regulate the apoptosis and proliferation of ovarian cancer cells (COV434) by regulating the interaction between 17β‐estradiol (E2) and insulin‐like growth factor‐1, without activating the ERK1/2 and phosphatidylinositol 3‐kinase (PI3K) pathways (Hoffmann et al, 2019; Kurowska et al, 2018). Moreover, apelin‐13 can promote the proliferation and metastasis of human prostate cancer (PCa) cells through an androgen receptor‐dependent mechanism or promoting the tumor to interact with the lymphatic system actively (Masoumi et al, 2020; Oliveira‐Ferrer et al, 2020; Y. Yang et al, 2016). After stromal cell‐derived factor‐1 (SDF‐1) or CXC chemokine receptor‐4 (CXCR4) treatment, the adhesion of PCa cells to osteosarcoma and ECs was significantly enhanced, and the ability to invade through the basement membrane was enhanced.…”

“…The combined application of anti‐vascular endothelial growth factor and apelin‐F13A can significantly reduce the angiogenesis and cell invasion ability of the GMB model, thereby further improving the effect of anti‐VEGF treatment and reduce side effects (Aldape et al, 2015; Amoozgar et al, 2019; Binda et al, 2017; Campos et al, 2010; Eskilsson et al, 2016; J. Yang et al, 2018). In breast cancer, Ovarian cancer, PCa and other cancers, apelin can also promote angiogenesis in tumors, showing strong angiogenic properties (Figure 3; Kurowska et al, 2018; Masoumi et al, 2020; Oliveira‐Ferrer et al, 2020; Peng et al, 2015; Sorli et al, 2007).…”

“…Moreover, apelin-13 can promote the proliferation and metastasis of human prostate cancer (PCa) cells through an androgen receptordependent mechanism or promoting the tumor to interact with the lymphatic system actively (Masoumi et al, 2020;Oliveira-Ferrer et al, 2020;Y. Yang et al, 2016).…”