A Novel Invadopodia-Specific Marker for Invasive and Pro-Metastatic Cancer Stem Cells

IntroductionStem-like cancer cells or cancer stem cells (CSCs) may comprise a phenotypically and functionally heterogeneous subset of cells, whereas the molecular markers reflecting this CSC hierarchy remain elusive. The glycolytic enzyme alpha-enolase (ENO1) present on the surface of malignant tumor cells has been identified as a metastasis-promoting factor through its function of activating plasminogen. The expression pattern of surface ENO1 (sENO1) concerning cell-to-cell or CSC heterogeneity and its functional roles await further investigation.MethodsThe cell-to-cell expression heterogeneity of sENO1 was profiled in malignant cells from different types of cancers using flow cytometry. The subcellular localization of sENO1 and its functional roles in the invadopodia formation and cancer cell invasiveness were investigated using a series of imaging, molecular, and in vitro and in vivo functional studies.ResultsWe showed here that ENO1 is specifically localized to the invadopodial surface of a significant subset (11.1%-63.9%) of CSCs in human gastric and prostate adenocarcinomas. sENO1+ CSCs have stronger mesenchymal properties than their sENO1- counterparts. The subsequent functional studies confirmed the remarkable pro-invasive and pro-metastatic capacities of sENO1+ CSCs. Mechanistically, inhibiting the surface localization of ENO1 by downregulating caveolin-1 expression compromised invadopodia biogenesis, proteolysis, and CSC invasiveness.ConclusionsOur study identified the specific expression of ENO1 on the invadopodial surface of a subset of highly invasive and pro-metastatic CSCs. sENO1 may provide a diagnostically and/or therapeutically exploitable target to improve the outcome of patients with aggressive and metastatic cancers

Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy–treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif–positive (ELR(+)) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR(+) chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy

Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events

Abnormal differentiation and growth of hematopoietic stem cells cause the development of hematopoietic diseases and hematopoietic malignancies. However, the molecular events underlying leukemia development are not well understood. In our recent study, we have demonstrated that calcium ionophore and phorbol ester force the differentiation of T lymphoblastic leukemia. The event involves a newly identified IκBα/WWOX/ERK signaling, in which WWOX is Ser14 phosphorylated. Additional evidence also reveals that pS14-WWOX is involved in enhancing cancer progression and metastasis and facilitating neurodegeneration. In this mini-review, we update the current knowledge for the functional roles of WWOX under physiological and pathological settings, and provide new insights regarding pS14-WWOX in T leukemia cell maturation, and switching the anticancer pY33-WWOX to pS14-WWOX for cancer promotion and disease progression. Impact statement WWOX was originally designated as a tumor suppressor. However, human newborns deficient in WWOX do not spontaneously develop tumors. Activated WWOX with Tyr33 phosphorylation is present in normal tissues and organs. However, when pY33-WWOX is overly induced under stress conditions, it becomes apoptotic to eliminate damaged cells. Notably, WWOX with Ser14 phosphorylation is upregulated in the lesions of cancer, as well as in the brain hippocampus and cortex with Alzheimer's disease. Suppression of pS14-WWOX by Zfra reduces cancer growth and mitigates Alzheimer's disease progression, suggesting that pS14-WWOX facilitates disease progression. pS14-WWOX can be regarded as a marker of disease progression

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

The ubiquitin-proteasome system (UPS) governs the protein degradation process and balances proteostasis and cellular homeostasis. It is a well-controlled mechanism, in which removal of the damaged or excessive proteins is essential in driving signal pathways for cell survival or death. Accumulation of damaged proteins and failure in removal may contribute to disease initiation such as in cancers and neurodegenerative diseases. In this notion, specific protein-protein interaction is essential for the recognition of targeted proteins in UPS. WW domain plays an indispensable role in the protein-protein interactions during signaling. Among the 51 WW domain-containing proteins in the human proteomics, near one-quarter of them are involved in the UPS, suggesting that WW domains are crucial modules for driving the protein-protein binding and subsequent ubiquitination and degradation. In this review, we detail a broad spectrum of WW domains in protein-protein recognition, signal transduction, and relevance to diseases. New perspectives in dissecting the molecular interactions are provided