Moving targets: Emerging roles for MMPs in cancer progression and metastasis

Matrix metalloproteinases have long been associated with cancer. Clinical trials of small molecule inhibitors for this family of enzymes however, were spectacularly unsuccessful in a variety of tumor types. Here, we discuss some of the newer roles that have been uncovered for MMPs in cancer that would not have been targeted with those initial inhibitors or in the patient populations analyzed. We also consider novel ways of using cancer-associated MMP activity for clinical benefit.     

Emerging roles for cancer registries in cancer control

Cancer registries are a vital part of the national cancer effort to cut United States cancer mortality rates in half by the year 2000. Registries provide the data to focus programs and monitor progress. Success in meeting the year 2000 goal will require aggressive attention to the opportunities for prevention, early detection, treatment, and applied cancer control research, all of which complement the current emphasis on basic research.     

Emerging roles for Rab family GTPases in human cancer

Members of the Ras-associated binding (Rab) family of small GTPases function as molecular switches regulating vesicular transport in eukaryotes cells. Their pathophysiological roles in human malignancies are less well-known compared to members of Ras and Rho families. Several members of the Rab family have, however, been shown to be aberrantly expressed in various cancer tissues. Recent findings have also revealed, in particular, Rab25 as a determinant of tumor progression and aggressiveness of epithelial cancers. Rab25 associates with α5β1 integrin, and enhances tumor cell invasion by directing the localization of integrin-containing vesicles to the leading edge of matrix invading pseudopodia. We summarized here recent findings on Rab25 and other Rabs implicated to be involved in a variety of human cancers, and discussed plausible mechanisms of how dysregulation of Rab expression could be tumorigenic or tumor suppressive.     

Emerging roles of HOTAIR in human cancer

Long noncoding RNA HOX antisense intergenic RNA (HOTAIR) is overexpressed in many types of cancers, and substantial evidence has suggested a link between cancers and HOTAIR. In the present study, we reviewed the structure and the corresponding biologic function of HOTAIR to clarify its molecular mechanism in cancer progression. HOTAIR promotes proliferation, invasion, and migration, and inhibits apoptosis in cancer cells. HOTAIR also participates in the pathogenesis and progression of cancer by regulating inflammation and immune signaling. These findings suggested that HOTAIR is a novel biomarker in human cancers.     

Emerging roles of PDGF-D signaling pathway in tumor development and progression

Platelet-derived growth factor-D (PDGF-D) can regulate many cellular processes, including cell proliferation, apoptosis, transformation, migration, invasion, angiogenesis and metastasis. Therefore PDGF-D signaling has been considered to be important in human malignancies, and thus PDGF-D signaling may represent a novel therapeutic target, and as such suggests that the development of agents that will target PDGF-D signaling is likely to have a significant therapeutic impact on human cancers. This mini-review describes the mechanisms of signal transduction associated with PDGF-D signaling to support the role of PDGF-D in the carcinogenesis. Moreover, we summarize data on several PDGF-D inhibitors especially naturally occurring “chemopreventive agent” such an indole compound, which we believe could serve as a novel agent for the prevention of tumor progression and/or treatment of human malignancies by targeted inactivation of PDGF-D signaling.     

Emerging roles of angiopoietin-like 4 in human cancer

Angiopoietin-like 4 (ANGPTL4) is best known for its role as an adipokine involved in the regulation of lipid and glucose metabolism. The characterization of ANGPTL4 as an adipokine is largely due to our limited understanding of the interaction partners of ANGPTL4 and how ANGPTL4 initiates intracellular signaling. Recent findings have revealed a critical role for ANGPTL4 in cancer growth and progression, anoikis resistance, altered redox regulation, angiogenesis, and metastasis. Emerging evidence suggests that ANGPTL4 function may be drastically altered depending on the proteolytic processing and posttranslational modifications of ANGPTL4, which may clarify several conflicting roles of ANGPTL4 in different cancers. Although the N-terminal coiled-coil region of ANGPTL4 has been largely responsible for the endocrine regulatory role in lipid metabolism, insulin sensitivity, and glucose homeostasis, it has now emerged that the COOH-terminal fibrinogen-like domain of ANGPTL4 may be a key regulator in the multifaceted signaling during cancer development. New insights into the mechanistic action of this functional domain have opened a new chapter into the possible clinical application of ANGPTL4 as a promising candidate for clinical intervention in the fight against cancer. This review summarizes our current understanding of ANGPTL4 in cancer and highlights areas that warrant further investigation. A better understanding of the underlying cellular and molecular mechanisms of ANGPTL4 will reveal novel insights into other aspects of tumorigenesis and the potential therapeutic value of ANGPTL4.     

Complex roles of nicotinamide N-methyltransferase in cancer progression

Nicotinamide N-methyltransferase (NNMT) is an intracellular methyltransferase, catalyzing the N-methylation of nicotinamide (NAM) to form 1-methylnicotinamide (1-MNAM), in which S-adenosyl-l-methionine (SAM) is the methyl donor. High expression of NNMT can alter cellular NAM and SAM levels, which in turn, affects nicotinamide adenine dinucleotide (NAD⁺)-dependent redox reactions and signaling pathways, and remodels cellular epigenetic states. Studies have revealed that NNMT plays critical roles in the occurrence and development of various cancers, and analysis of NNMT expression levels in different cancers from The Cancer Genome Atlas (TCGA) dataset indicated that NNMT might be a potential biomarker and therapeutic target for tumor diagnosis and treatment. This review provides a comprehensive understanding of recent advances on NNMT functions in different tumors and deciphers the complex roles of NNMT in cancer progression.Subject terms: Cancer, Mechanisms of disease     

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

A disintegrin and metalloproteinases (ADAMs) are a recently discovered family of proteins that share the metalloproteinase domain with matrix metalloproteinases (MMPs). Among this family, structural features distinguish the membrane-anchored ADAMs and the secreted ADAMs with thrombospondin motifs referred to as ADAMTSs. By acting on a large panel of membrane-associated and extracellular substrates, they control several cell functions such as adhesion, fusion, migration and proliferation. The current review addresses the contribution of these proteinases in the positive and negative regulation of cancer progression as mainly mediated by the regulation of growth factor activities and integrin functions.     

Emerging roles of protein kinase D1 in cancer

Protein kinase D1 (PKD1) is a serine-threonine kinase that regulates various functions within the cell, including cell proliferation, apoptosis, adhesion, and cell motility. In normal cells, this protein plays key roles in multiple signaling pathways by relaying information from the extracellular environment and/or upstream kinases and converting them into a regulated intracellular response. The aberrant expression of PKD1 is associated with enhanced cancer phenotypes, such as deregulated cell proliferation, survival, motility, and epithelial mesenchymal transition. In this review, we summarize the structural and functional aspects of PKD1 and highlight the pathobiological roles of this kinase in cancer.     

Multiple roles for basement membrane proteins in cancer progression and EMT

Metastasis or the progression of malignancy poses a major challenge in cancer therapy and is the principal reason for increased mortality. The epithelial-mesenchymal transition (EMT) of the basement membrane (BM) allows cells of epithelial phenotype to transform into a mesenchymal-like (quasi-mesenchymal) phenotype and metastasize via the lymphovascular system through a metastatic cascade by intravasation and extravasation. This helps in the progression of carcinoma from the primary site to distant organs. Collagen, laminin, and integrin are the prime components of BM and help in tumor cell metastasis, which makes them ideal cancer drug targets. Further, recent studies have shown that collagen, laminin, and integrin can be used as a biomarker for metastatic cells. In this review, we have summarized the current knowledge of such therapeutics, which are either currently in preclinical or clinical stages and could be promising cancer therapeutics.Data availabilityNot applicable     

Emerging roles for phospholipase A2 enzymes in cancer

Phospholipase A₂ (PLA₂) enzymes (EC3.1.4.4) regulate the release of biologically active fatty acids and lysophospholipids from membrane phospholipid pools. These lipids are also substrates for intracellular biochemical pathways that generate potent autocrine and paracrine lipid mediators such as the eicosanoids and platelet activating factor. These factors, in turn, regulate cell proliferation, survival, differentiation, motility, tissue vascularisation, and immune surveillance in virtually all tissues, functions that are subverted by cancer cells for tumour growth and metastasis. Thus the relevance of PLA₂-dependent pathways to the genesis and progression of cancer has been of interest since their discovery and with recent technological advances, their role in tumourigenesis has become more tractable experimentally. Limited human genetic studies have not yet identified PLA₂ enzymes as classical mutated oncogenes or tumour suppressor genes. However, there is strong evidence that of the 22 identified human PLA₂ enzymes, ten of which have been studied in cancer to date, most are aberrantly expressed in a proportion of tumours derived from diverse organs. Correlative and functional studies implicate the expression of some secreted enzymes (sPLA₂s), particularly the best studied enzyme Group IIA sPLA₂ in either tumour promotion or inhibition, depending on the organ involved and the biochemical microenvironment of tumours. As in immune-mediated inflammatory pathologies, genetic deletion studies in mice, supported by limited studies with human cells and tissues, have identified an important role for Group IVA PLA₂ in regulating certain cancers. Pharmacological intervention studies in prostate cancer suggest that hGIIA-dependent tumour growth is dependent on indirect regulation of Group IVA PLA₂. Group VI calcium-independent PLA₂ enzymes have also been recently implicated in tumourigenesis with in vitro studies suggesting multiple possible roles for these enzymes. Though apparently complex, further characterization of the regulatory relationships amongst PLA₂ enzymes, lipid mediator biosynthetic enzymes and the lipid mediators they produce during tumour progression is required to define the biochemical context in which the enzymes modulate cancer growth and development.     

Dual roles of CCN proteins in breast cancer progression

The tumor microenvironment has a powerful effect on the development and progression of human breast cancer, which may be used therapeutically. Despite efforts to understand the complex role of the tumor microenvironment in breast cancer development, the specific players and their contributions to tumorigenesis need further investigation. The CCN family of matricellular proteins comprises six members (CCN1–6; CYR61, CTGF, NOV, WISP1–3) with central roles in development, inflammation, and tissue repair. CCN proteins also exert functions during pathological processes including fibrosis and cancer by regulating extracellular signals in the cellular environment. Studies have demonstrated that all six CCN proteins exert functions in breast tumorigenesis. Although CCN proteins share a multimodular structure in which most cysteine residues are conserved within structural motifs, they may have opposing functions in breast cancer progression. A better understanding of the functions of each CCN member will assist in the development of specific therapeutic approaches for breast cancer.     

Emerging medicinal roles for lysophospholipid signaling

The two lysophospholipids (LPs) lysophosphatidic acid and sphingosine 1-phosphate (S1P) regulate diverse biological processes. Over the past decade, it has become clear that medically relevant LP activities are mediated by specific G protein-coupled receptors, implicating them in the etiology of a growing number of disorders. A new class of LP agonists shows promise for drug therapy: the experimental drug FTY720 is phosphorylated in vivo to produce a potent S1P receptor agonist (FTY720-P) and is currently in Phase III clinical trials for kidney transplantation and Phase II for multiple sclerosis. Recent genetic and pharmacological studies on LP signaling in animal disease models have identified new areas in which interventions in LP signaling might provide novel therapeutic approaches for the treatment of human diseases.