TGFβ signaling networks in ovarian cancer progression and plasticity

Abstract

Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. Late-stage diagnosis with significant tumor burden, accompanied by recurrence and chemotherapy resistance, contributes to this poor prognosis. These morbidities are known to be tied to events associated with epithelial-mesenchymal transition (EMT) in cancer. During EMT, localized tumor cells alter their polarity, cell–cell junctions, cell–matrix interactions, acquire motility and invasiveness and an exaggerated potential for metastatic spread. Key triggers for EMT include the Transforming Growth Factor-β (TGFβ) family of growth factors which are actively produced by a wide array of cell types within a specific tumor and metastatic environment. Although TGFβ can act as either a tumor suppressor or promoter in cancer, TGFβ exhibits its pro-tumorigenic functions at least in part via EMT. TGFβ regulates EMT both at the transcriptional and post-transcriptional levels as outlined here. Despite recent advances in TGFβ based therapeutics, limited progress has been seen for ovarian cancers that are in much need of new therapeutic strategies. Here, we summarize and discuss several recent insights into the underlying signaling mechanisms of the TGFβ isoforms in EMT in the unique metastatic environment of EOCs and the current therapeutic interventions that may be relevant.

Splice-Variant Knock-Out of TGFβ Receptors Perturbates the Proteome of Ovarian Carcinoma Cells

“…EMT a well-known process that occurs in cancer in general, and is known to be regulated by the TGFβ pathway [ 25 ]. As part of our objectives was studying the contribution of the splice variants to the progression of OC, we analyzed the expression of regulatory elements of the EMT process, namely, SNAIL and TWIST protein through Western Blot analysis and the lncRNA MALAT1 through qPCR.…”

Proteomics Analysis of Lymphatic Metastasis-Related Proteins Using Highly Metastatic Human Melanoma Cells Originated by Sequential <i>in Vivo</i> Implantation

“…Physiologically, IL13 is produced from activated T-helper 2 (Th2) cells, which stimulates immunoglobulin E isotype switching via the up-regulation of CD23 and major histocom- patibility complex (MHC) Class II. 18) When IL13RA2 binds to its ligand IL-13, the TGF-β promoter is activated and subsequently causes an increased level of expression of TGF-β. 19) TGF-β has a multifaceted effect on cancer progression and metastasis.…”

“…18) When IL13RA2 binds to its ligand IL-13, the TGF-β promoter is activated and subsequently causes an increased level of expression of TGF-β. 19) TGF-β has a multifaceted effect on cancer progression and metastasis. For example, in ovarian cancer, it has been reported that TGF-β induces cancer metastasis through promoting epithelial-mesenchymal transition (EMT).…”

“…For example, in ovarian cancer, it has been reported that TGF-β induces cancer metastasis through promoting epithelial-mesenchymal transition (EMT). 19) EMT is the process by which epithelial cancers (colon cancer, breast cancer, etc.) acquire mesenchymal cell-like properties.…”

PVT1, a YAP1 dependent stress responsive lncRNA drives ovarian cancer metastasis and chemoresistance

“…All subtypes are exposed to cellular stressors during metastasis that involve the ovaries, the omentum, and the peritoneum. The metastatic peritoneal spread involves cell-ECM detachment, loss of cell-cell contacts, epithelial-mesenchymal transition (EMT) and shedding of cells from the tumor, followed by anchorage independent survival, re-attachment to new locations and re-establishment of cell-cell contacts [6]. Primary tumors in the fallopian tube and ovaries and secondary peritoneal growths in the abdominal cavity can also be hypoxic [7], potentially further driving metastasis and chemoresistance in a feed forward manner [7, 8].…”