Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

Abstract

Ovarian carcinoma is associated with the highest death rate of all gynecological tumors. On one hand, its aggressiveness is based on the rapid dissemination of ovarian cancer cells to the peritoneum, the omentum, and organs located in the peritoneal cavity, and on the other hand, on the rapid development of resistance to chemotherapeutic agents. In this review, we focus on the metastatic process of ovarian cancer, which involves dissemination of, homing to and growth of tumor cells in distant organs, and describe promising molecular targets for possible therapeutic intervention. We provide an outline of the interaction of ovarian cancer cells with the microenvironment such as mesothelial cells, adipocytes, fibroblasts, endothelial cells, and other stromal components in the context of approaches for therapeutic interference with dissemination. The targets described in this review are discussed with respect to their validity as drivers of metastasis and to the availability of suitable efficient agents for their blockage, such as small molecules, monoclonal antibodies or antibody conjugates as emerging tools to manage this disease.

Keywords: Adipocytes; EOC; ascites; epithelial ovarian cancer Penzberg; growth of metastases; homing; mesothelial cells; peritoneal cells; review; therapeutic targets; transcoelomic dissemination.

Figure 1. Overview of targets involved in metastasis of ovarian cancer. Targets discussed in this review are shown. The inner circle represents an ovarian cancer cell and we highlight intracellular, transmembrane and glycophosphatidylinositol- anchored targets as well as ligands expressed by stromal cells or ovarian cancer cells as outer circles. The stromal ligands can be expressed by adipocytes, cancer-associated fibroblasts (CAF), endothelial cells, mesenterial cells or natural killer (NK) cells. A2B1, A3B1, A4B1, A5B1, A6B1: Integrins α2β1, α3β1, α4β1, α5β1, α6β1; CD44: cluster of differentiation 44; COL: collagen type IV; CX3CL1: C-X3-C motif ligand 1; CX3CR1: CX3C chemokine receptor 1; CXCL 11,12: CXC chemokine ligand 11,12; CXCR 3,4: CXC chemokine receptor 1,3, 4; FABP4: fatty-acid binding protein 4; FAS: fatty acid synthase; FGF: fibroblast growth factor; FGFR: FGF receptor; FN: fibronectin; HA: hyaluronic acid; HGF: hepatocyte growth factor; IL8: interleukin 8; KLK4-8, 10: kallikreins 4-8, 10; L1CAM: L1 cell adhesion molecule; LN: laminin; LTN: lymphotactin; MMP2/9: matrix metalloproteinase 2 or 9; MT-MMP1: membrane-type matrix metalloproteinase 1; MET: receptor tyrosine kinase 1; MLN: mesothelin; MUC16: mucin 16; PDGF-A: placental growth factor isoform A; PDGFR: PDGF receptor; SIGLEC 9: sialic acid recognizing immunoglobulin superfamily lectin 9; uPA: urokinase-type plasminogen activator; uPAR: urokinase plasminogen activator receptor; VCAM1: vascular cell adhesion molecule 1; VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; vitronectin: vitronectin; XCR1: lymphotactin receptor X chemokine receptor 1.

Figure 2. Expression of selected kallikrein (KLK) family members in normal ovarian tissues and ovarian tumors as measured by RNA sequencing of normal ovarian tissues (n=6) [Broad Genotype-Tissue Expression project (GTEX) atlas] (upper panel) and ovarian serous cystadenocarcinoma (n=216) from The Cancer Genome Atlas (TCGA) (lower panel). Expression values are given as log2 reads per kilobase per million mapped reads (RPKM) values for GTEX and as normalized read counts for the TCGA data (157). Expression values are therefore not directly comparable. The two red lines indicate low and high expression in the two datasets. Thresholds were set to an RPKM ≥1 for GTEX and a read count ≥100 for TCGA. Expression data are shown as box plots, where the black line represents the median, and the black rectangles show the upper and lower 25% quartile. Therefore, 50% of all data points are included in the black rectangle. All other data points, except for outliers, are located between the upper and lower whiskers.

Figure 3. Expression of L1 cell adhesion molecule (L1CAM), transmembrane tyrosine kinase c-MET proto-oncogene product (MET) and mucin 16 (MUC16) in normal ovarian tissues and ovarian tumors. Expression, as measured by RNA sequencing of normal ovarian tissues (n=6) [Broad Genotype-Tissue Expression project (GTEX) atlas] and ovarian serous cystadenocarcinoma (n=216) from The Cancer Genome Atlas (TCGA) are shown in the upper and lower panel, respectively. For GTEX, expression values are given as log2 reads per kilobase per million mapped reads (RPKM) values and as normalized read counts for the TCGA data (157). Expression levels are, therefore, not directly comparable. The two red lines indicate low and high expression in the two datasets. Thresholds have been set to an RPKM ≥1 for GTEX and Read Count ≥100 for TCGA. Expression data are shown as box plots where the black line represents the median and the black rectangles show the upper and lower 25% quartile. Therefore, 50% of all data points are included in the black rectangle. All other data points, except for outliers are located between the upper and lower whiskers.