Cancer and Metastasis Reviews

Preface

Correction to: mTOR co-targeting strategies for head and neck cancer therapy The author’s name was tagged incorrectly in XML. “Silvio Gutkind J” should be tagged as “J. Silvio Gutkind”. Given name is “J. Silvio” and the Family name is “Gutkind”.

Biography—Robert J. Gillies

Correction to: Tumor pH and metastasis: a malignant process beyond hypoxia The authors have noticed a typographical error in the published article. The term “epithelial-to-mesenchymal transition” should have been used instead of the term “endothelial-to-mesenchymal transition” throughout the manuscript.

What is pH regulation, and why do cancer cells need it? Abstract Metabolism is a continuous source of acids. To keep up with a desired metabolic rate, tumors must establish an adequate means of clearing their acidic end-products. This homeostatic priority is achieved by various buffers, enzymes, and transporters connected through the common denominator of H+ ions. Whilst this complexity is proportionate to the importance of adequate pH control, it is problematic for developing an intuition for tracking the route taken by acids, assessing the relative importance of various acid-handling proteins, and predicting the outcomes of pharmacological inhibition or genetic alteration. Here, with the help of a simplified mathematical framework, the genesis of cancer pH regulation is explained in terms of the obstacles to efficient acid venting and how these are overcome by specific molecules, often associated with cancer. Ultimately, the pH regulatory apparatus in tumors must (i) provide adequate lactic acid permeability through membranes, (ii) facilitate CO2/HCO3−/H+ diffusivity across the interstitium, (iii) invest in a form of active transport that strikes a favorable balance between intracellular pH and intracellular lactate retention under the energetic constraints of a cell, and (iv) enable the necessary feedback to complete the homeostatic loop. A more informed and quantitative approach to understanding acid-handling in cancer is mandatory for identifying vulnerabilities, which could be exploited as therapeutic targets.

Fugitives on the run: circulating tumor cells (CTCs) in metastatic diseases Abstract The presence of circulating tumor cells (CTCs) in the bloodstream signals the existence of a tumor and denotes risk of metastatic spread. CTCs can be isolated and analyzed to monitor cancer progression and therapeutic response. However, CTC isolation devices have shown considerable variation in detection rates, limiting their use as a routine diagnostic and monitoring tool. In this review, we discuss recent advances in CTC detection methodologies and associated clinical studies. We provide perspective on the future direction of CTC isolation and molecular characterization towards developing reliable biomarkers that monitor disease progression or therapeutic response.

Extracellular acidity and increased exosome release as key phenotypes of malignant tumors Abstract The tumor milieu is characteristically acidic as a consequence of the fermentative metabolism of glucose that results in massive accumulation of lactic acid within the cytoplasm. Tumor cells get rid of excessive protons through exchangers that are responsible for the extracellular acidification that selects cellular clones that are more apt at surviving in this challenging and culling environment. Extracellular vesicles (EVs) are vesicles with diameters ranging from nm to μm that are released from the cells to deliver nucleic acids, proteins, and lipids to adjacent or distant cells. EVs are involved in a plethora of biological events that promote tumor progression including unrestricted proliferation, angiogenesis, migration, local invasion, preparation of the metastatic niche, metastasis, downregulation or hijacking of the immune system, and drug resistance. There is evidence that the release of specific exosomes is increased many folds in cancer patients, as shown by many techniques aimed at evaluating “liquid biopsies”. The quality of the exosomal contents has been shown to vary at the different moments of tumor life such as local invasion or metastasis. In vitro studies have recently pointed out that cancer acidity is a major determinant in inducing increased exosome release by human cancer cells, by showing that exosomal release was increased as the pH moved from 7.4 pH to the typical pH of cancer that is 6.5. In this review, we emphasize the recent evidence that tumor acidity and exosomes levels are strictly related and strongly contribute to the malignant tumor phenotypes.

Cause and effect of microenvironmental acidosis on bone metastases Abstract Skeletal involvement is a frequent and troublesome complication in advanced cancers. In the process of tumor cells homing to the skeleton to form bone metastases (BM), different mechanisms allow tumor cells to interact with cells of the bone microenvironment and seed in the bone tissue. Among these, tumor acidosis has been directly associated with tumor invasion and aggressiveness in several types of cancer although it has been less explored in the context of BM. In bone, the association of local acidosis and cancer invasiveness is even more important for tumor expansion since the extracellular matrix is formed by both organic and hard inorganic matrices and bone cells are used to sense protons and adapt or react to a low pH to maintain tissue homeostasis. In the BM microenvironment, increased concentration of protons may derive not only from glycolytic tumor cells but also from tumor-induced osteoclasts, the bone-resorbing cells, and may influence the progression or symptoms of BM in many different ways, by directly enhancing cancer cell motility and aggressiveness, or by modulating the functions of bone cells versus a pro-tumorigenic phenotype, or by inducing bone pain. In this review, we will describe and discuss the cause of acidosis in BM, its role in BM microenvironment, and which are the final effectors that may be targeted to treat metastatic patients.

Mucin glycoproteins block apoptosis; promote invasion, proliferation, and migration; and cause chemoresistance through diverse pathways in epithelial cancers Abstract Overexpression of mucin glycoproteins has been demonstrated in many epithelial-derived cancers. The significance of this overexpression remains uncertain. The aim of this paper was to define the association of mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers by performing a systematic review of all published data. A systematic review of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was performed to identify all papers that evaluated the association between mucin glycoproteins with apoptosis, cell growth, invasion, migration, adhesion, and clonogenicity in vitro as well as tumor growth, tumorigenicity, and metastasis in vivo in epithelial-derived cancers. PRISMA guidelines were adhered to. Results of individual studies were extracted and pooled together based on the organ in which the cancer was derived from. The initial search revealed 2031 papers, of which 90 were deemed eligible for inclusion in the study. The studies included details on MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16. The majority of studies evaluated MUC1. MUC1 overexpression was consistently associated with resistance to apoptosis and resistance to chemotherapy. There was also evidence that overexpression of MUC2, MUC4, MUC5AC, MUC5B, MUC13, and MUC16 conferred resistance to apoptosis in epithelial-derived cancers. The overexpression of mucin glycoproteins is associated with resistance to apoptosis in numerous epithelial cancers. They cause resistance through diverse signaling pathways. Targeting the expression of mucin glycoproteins represents a potential therapeutic target in the treatment of epithelial-derived cancers.

Pro-metastatic functions of lipoproteins and extracellular vesicles in the acidic tumor microenvironment Abstract Although the overall mortality in cancer is steadily decreasing, major groups of patients still respond poorly to available treatments. The key clinical challenge discussed here relates to the inherent capacity of cancer cells to metabolically adapt to hypoxic and acidic stress, resulting in treatment resistance and a pro-metastatic behavior. Hence, a detailed understanding of stress adaptive responses is critical for the design of more rational therapeutic strategies for cancer. We will focus on the emerging role of extracellular vesicles (EVs) and lipoprotein particles in cancer cell metabolic stress adaptation and how these pathways may constitute potential Achilles’ heels of the cancer cell machinery and alternative treatment targets of metastasis. In this context, common extracellular lipid uptake mechanisms, involving specific cell-surface receptors and endocytic pathways, may operate during remodeling of acidic atherosclerotic plaques as well as the tumor microenvironment. The role of endocytosis in regulating the cellular response to hypoxic and acidic stress through spatial coordination of receptor proteins may be exploited for therapeutic purposes. As a consequence, molecular mechanisms of endocytosis have attracted increasing attention as potential targets for tumor specific delivery of therapeutic substances, such as antibody–drug conjugates. The identification of internalizing surface proteins specific to the acidic tumor niche remains an unmet need of high clinical relevance. Among the currently explored, acidosis-related, internalizing target proteins, we will focus on the cell-surface proteoglycan carbonic anhydrase 9.