Targeting receptor tyrosine kinases in ovarian cancer: Genomic dysregulation, clinical evaluation of inhibitors, and potential for combinatorial therapies.

Epithelial ovarian cancer (EOC) remains one of the leading causes of cancer-related deaths among women worldwide. Receptor tyrosine kinases (RTKs) have long been sought as therapeutic targets for EOC, as they are frequently hyperactivated in primary tumors and drive disease relapse, progression, and metastasis. More recently, these oncogenic drivers have been implicated in EOC response to poly(ADP-ribose) polymerase (PARP) inhibitors and epigenome-interfering agents. This evidence revives RTKs as promising targets for therapeutic intervention of EOC. This review summarizes recent studies on the role of RTKs in EOC malignancy and the use of their inhibitors for clinical treatment. Our focus is on the ERBB family, c-Met, and VEGFR, as they are linked to drug resistance and targetable using commercially available drugs. The importance of these RTKs and their inhibitors is highlighted by their impact on signal transduction and intratumoral heterogeneity in EOC and successful use as maintenance therapy in the clinic through suppression of the VEGF/VEGFR axis. Finally, the therapeutic potential of RTK inhibitors is discussed in the context of combinatorial targeting via co-inhibiting proliferative and anti-apoptotic pathways, epigenomic/transcriptional programs, and harnessing the efficacy of PARP inhibitors and programmed cell death 1/ligand 1 immune checkpoint therapies.

The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis.

As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), and the Wnt/ß-catenin pathway, as well as the dynamics of exosome and cellular metabolism. Finally, we discuss the implications of the highly plastic nature and epigenetic susceptibility of CD151 expression, function, and signaling for clinical diagnosis and therapeutic intervention for human cancer.

CD151-α3ß1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion.

Glioblastoma, one of the most aggressive forms of brain cancer, is featured by high tumor cell motility and invasiveness, which not only fuel tumor infiltration, but also enable escape from surgical or other clinical interventions. Thus, better understanding of how these malignant traits are controlled will be key to the discovery of novel biomarkers and therapies against this deadly disease. Tetraspanin CD151 and its associated α3ß1 integrin have been implicated in facilitating tumor progression across multiple cancer types. How these adhesion molecules are involved in the progression of glioblastoma, however, remains largely unclear. Here, we examined an in-house tissue microarray-based cohort of 96 patient biopsies and TCGA dataset to evaluate the clinical significance of CD151 and α3ß1 integrin. Functional and signaling analyses were also conducted to understand how these molecules promote the aggressiveness of glioblastoma at molecular and cellular levels. Results from our analyses showed that CD151 and α3 integrin were significantly elevated in glioblastomas at both protein and mRNA levels, and exhibited strong inverse correlation with patient survival (p < 0.006). These adhesion molecules also formed tight protein complexes and synergized with EGF/EGFR to accelerate tumor cell motility and invasion. Furthermore, disruption of such complexes enhanced the survival of tumor-bearing mice in a xenograft model, and impaired activation of FAK and small GTPases. Also, knockdown- or pharmacological agent-based attenuation of EGFR, FAK or Graf (ARHGAP26)/small GTPase-mediated pathways markedly mitigated the aggressiveness of glioblastoma cells. Collectively, our findings provide clinical, molecular and cellular evidence of CD151-α3ß1 integrin complexes as promising prognostic biomarkers and therapeutic targets for glioblastoma.

CD151 represses mammary gland development by maintaining the niches of progenitor cells.

Tetraspanin CD151 interacts with laminin-binding integrins (i.e., α3ß1, α6ß1 and α6ß4) and other cell surface molecules to control diverse cellular and physiological processes, ranging from cell adhesion, migration and survival to tissue architecture and homeostasis. Here, we report a novel role of CD151 in maintaining the branching morphogenesis and activity of progenitor cells during the pubertal development of mammary glands. In contrast to the disruption of laminin-binding integrins, CD151 removal in mice enhanced the tertiary branching in mammary glands by 2.4-fold and the number of terminal end buds (TEBs) by 30%, while having minimal influence on either primary or secondary ductal branching. Consistent with these morphological changes are the skewed distribution of basal/myoepithelial cells and a 3.2-fold increase in proliferating Ki67-positive cells. These novel observations suggest that CD151 impacts the branching morphogenesis of mammary glands by upregulating the activities of bipotent progenitor cells. Indeed, our subsequent analyses indicate that upon CD151 removal the proportion of CD24(Hi)CD49f(Low) progenitor cells in the mammary gland increased by 34%, and their proliferating and differentiating activities were significantly upregulated. Importantly, fibronectin, a pro-branching extracellular matrix (ECM) protein deposited underlying mammary epithelial or progenitor cells, increased by >7.2-fold. Moreover, there was a concomitant increase in the expression and nuclear distribution of Slug, a transcription factor implicated in the maintenance of mammary progenitor cell activities. Taken together, our studies demonstrate that integrin-associated CD151 represses mammary branching morphogenesis by controlling progenitor cell activities, ECM integrity and transcription program.

CD151-α3ß1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling.

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3ß1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated. Knocking down Slug partially restores CD151-α3ß1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of ß-catenin and Axin-2 as well as resistance to the inhibition in ß-catenin-dependent transcriptional complexes. Together, our study demonstrates that CD151-α3ß1 integrin complexes regulate ovarian tumor growth by repressing Slug-mediated EMT and Wnt signaling.

Integrin-associated CD151 drives ErbB2-evoked mammary tumor onset and metastasis.

ErbB2+ human breast cancer is a major clinical problem. Prior results have suggested that tetraspanin CD151 might contribute to ErbB2-driven breast cancer growth, survival, and metastasis. In other cancer types, CD151 sometimes supports tumor growth and metastasis. However, a definitive test of CD151 effects on de novo breast cancer initiation, growth, and metastasis has not previously been done. We used CD151 gene-deleted mice expressing the MMTV-ErbB2 transgene to show that CD151 strongly supports ErbB2+ mammary tumor initiation and metastasis. Delayed tumor onset (by 70-100 days) in the absence of CD151 was accompanied by reduced survival of mammary epithelial cells and impaired activation of FAK- and MAPK-dependent pathways. Both primary tumors and metastatic nodules showed smooth, regular borders, consistent with a less invasive phenotype. Furthermore, consistent with impaired oncogenesis and decreased metastasis, CD151-targeted MCF-10A/ErbB2 cells showed substantial decreases in three-dimensional colony formation, EGF-stimulated tumor cell motility, invasion, and transendothelial migration. These CD151-dependent functions were largely mediated through α6ß4 integrin. Moreover, CD151 ablation substantially prevented PKC- and EGFR/ERK-dependent α6ß4 integrin phosphorylation, consistent with retention of epithelial cell polarity and intermediate filament cytoskeletal connections, which helps to explain diminished metastasis. Finally, clinical data analyses revealed a strong correlation between CD151 and ErbB2 expression and metastasis-free survival of breast cancer patients. In conclusion, we provide strong evidence that CD151 collaborates with LB integrins (particularly α6ß4 and ErbB2 (and EGFR) receptors to regulate multiple signaling pathways, thereby driving mammary tumor onset, survival, and metastasis. Consequently, CD151 is a useful therapeutic target in malignant ErbB2+ breast cancer.