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EpCAM (epithelial cell adhesion molecule) was discovered four decades ago as a tumor antigen on colorectal carcinomas. Owing to its frequent and high expression on carcinomas and their metastases, EpCAM serves as a prognostic marker, a therapeutic target, and an anchor molecule on circulating and disseminated tumor cells (CTCs/DTCs), which are considered the major source for metastatic cancer cells. Today, EpCAM is reckoned as a multi-functional transmembrane protein involved in the regulation of cell adhesion, proliferation, migration, stemness, and epithelial-to-mesenchymal transition (EMT) of carcinoma cells. To fulfill these functions, EpCAM is instrumental in intra- and intercellular signaling as a full-length molecule and following regulated intramembrane proteolysis, generating functionally active extra- and intracellular fragments. Intact EpCAM and its proteolytic fragments interact with claudins, CD44, E-cadherin, epidermal growth factor receptor (EGFR), and intracellular signaling components of the WNT and Ras/Raf pathways, respectively. This plethora of functions contributes to shaping intratumor heterogeneity and partial EMT, which are major determinants of the clinical outcome of carcinoma patients. EpCAM represents a marker for the epithelial status of primary and systemic tumor cells and emerges as a measure for the metastatic capacity of CTCs. Consequentially, EpCAM has reclaimed potential as a prognostic marker and target on primary and systemic tumor cells.

Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.

Lung cancer is one of the most common diseases among humans and one of the major causes of growing mortality. Medical experts believe that diagnosing lung cancer in the early phase can reduce death with the illustration of lung nodule through computed tomography (CT) screening. Examining the vast amount of CT images can reduce the risk. However, the CT scan images incorporate a tremendous amount of information about nodules, and with an increasing number of images make their accurate assessment very challenging tasks for radiologists. Recently, various methods are evolved based on handcraft and learned approach to assist radiologists. In this paper, we reviewed different promising approaches developed in the computer-aided diagnosis (CAD) system to detect and classify the nodule through the analysis of CT images to provide radiologists’ assistance and present the comprehensive analysis of different methods.

While various clinical applications especially in oncology are now in progress such as diagnosis, prognosis, therapy monitoring, or patient follow-up, the determination of structural characteristics of cell-free circulating DNA (cirDNA) are still being researched. Nevertheless, some specific structures have been identified and cirDNA has been shown to be composed of many “kinds.” This structural description goes hand-in-hand with the mechanisms of its origins such as apoptosis, necrosis, active release, phagocytosis, and exocytose. There are multiple structural forms of cirDNA depending upon the mechanism of release: particulate structures (exosomes, microparticles, apoptotic bodies) or macromolecular structures (nucleosomes, virtosomes/proteolipidonucleic acid complexes, DNA traps, links with serum proteins or to the cell-free membrane parts). In addition, cirDNA concerns both nuclear and/or mitochondrial DNA with both species exhibiting different structural characteristics that potentially reveal different forms of biological stability or diagnostic significance. This review focuses on the origins, structures and functional aspects that are paradoxically less well described in the literature while numerous reviews are directed to the clinical application of cirDNA. Differentiation of the various structures and better knowledge of the fate of cirDNA would considerably expand the diagnostic power of cirDNA analysis especially with regard to the patient follow-up enlarging the scope of personalized medicine. A better understanding of the subsequent fate of cirDNA would also help in deciphering its functional aspects such as their capacity for either genometastasis or their pro-inflammatory and immunological effects.

Mucins (MUC) protect epithelial barriers from environmental insult to maintain homeostasis. However, their aberrant overexpression and glycosylation in various malignancies facilitate oncogenic events from inception to metastasis. Mucin-associated sialyl-Tn (sTn) antigens bind to various receptors present on the dendritic cells (DCs), macrophages, and natural killer (NK) cells, resulting in overall immunosuppression by either receptor masking or inhibition of cytolytic activity. MUC1-mediated interaction of tumor cells with innate immune cells hampers cross-presentation of processed antigens on MHC class I molecules. MUC1 and MUC16 bind siglecs and mask Toll-like receptors (TLRs), respectively, on DCs promoting an immature DC phenotype that in turn reduces T cell effector functions. Mucins, such as MUC1, MUC2, MUC4, and MUC16, interact with or form aggregates with neutrophils, macrophages, and platelets, conferring protection to cancer cells during hematological dissemination and facilitate their spread and colonization to the metastatic sites. On the contrary, poor glycosylation of MUC1 and MUC4 at the tandem repeat region (TR) generates cancer-specific immunodominant epitopes. The presence of MUC16 neo-antigen-specific T cell clones and anti-MUC1 antibodies in cancer patients suggests that mucins can serve as potential targets for developing cancer therapeutics. The present review summarizes the molecular events involved in mucin-mediated immunomodulation, and metastasis, as well as the utility of mucins as targets for cancer immunotherapy and radioimmunotherapy.

Trafficking of biological material across membranes is an evolutionary conserved mechanism and is part of any normal cell homeostasis. Such transport is composed of active, passive, export through microparticles, and vesicular transport (exosomes) that collectively maintain proper compartmentalization of important micro- and macromolecules. In pathological states, such as cancer, aberrant activity of the export machinery results in expulsion of a number of key proteins and microRNAs resulting in their misexpression. Exosome-mediated expulsion of intracellular drugs could be another barrier in the proper action of most of the commonly used therapeutics, targeted agents, and their intracellular metabolites. Over the last decade, a number of studies have revealed that exosomes cross-talk and/or influence major tumor-related pathways, such as hypoxia-driven epithelial-to-mesenchymal transition, cancer stemness, angiogenesis, and metastasis involving many cell types within the tumor microenvironment. Emerging evidence suggests that exosome-secreted proteins can also propel fibroblast growth, resulting in desmoplastic reaction, a major barrier in effective cancer drug delivery. This comprehensive review highlights the advancements in the understanding of the biology of exosomes secretions and the consequence on cancer drug resistance. We propose that the successful combination of cancer treatments to tackle exosome-mediated drug resistance requires an interdisciplinary understanding of these cellular exclusion mechanisms, and how secreted biomolecules are involved in cellular cross-talk within the tumor microenvironment.

Resistance to therapy is one of the prime causes for treatment failure in cancer and recurrent disease. In recent years, autophagy has emerged as an important cell survival mechanism in response to different stress conditions that are associated with cancer treatment and aging. Autophagy is an evolutionary conserved catabolic process through which damaged cellular contents are degraded after uptake into autophagosomes that subsequently fuse with lysosomes for cargo degradation, thereby alleviating stress. In addition, autophagy serves to maintain cellular homeostasis by enriching nutrient pools. Although autophagy can act as a double-edged sword at the interface of cell survival and cell death, increasing evidence suggest that in the context of cancer therapy-induced stress responses, it predominantly functions as a cell survival mechanism. Here, we provide an up-to-date overview on our current knowledge of the role of pro-survival autophagy in cancer therapy at the preclinical and clinical stages and delineate the molecular mechanisms of autophagy regulation in response to therapy-related stress conditions. A better understanding of the interplay of cancer therapy and autophagy may allow to unveil new targets and avenues for an improved treatment of therapy-resistant tumors in the foreseeable future.

Cancer is a systemic disease encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion, and metastasis. In breast cancer, CAFs not only promote tumor progression but also induce therapeutic resistance. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistance. This review summarizes the current understandings of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. In addition, the effects of other stromal components such as endothelial cells, macrophages, and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to categorize patients into a specific and confirmed subtype for personalized treatment.

With the length of about 26–31 nt, PIWI-interacting RNA (piRNA) is a small non-coding RNA (ncRNA) that interacts with PIWI proteins to form the piRNA silencing complex (piRISC). PIWI is a subfamily of Argonaute, and piRNA must bind to PIWI to exert its regulatory role. Current studies indicated that piRNA and PIWI are significantly abnormally expressed in gastric, breast, kidney, colon, and lung cancers, and are involved in the initiation, progression, and metastasis of cancers, which may be the potential diagnostic tools, prognostic markers, and therapeutic targets for cancers. By reviewing piRNA recent studies, this research summarized the mechanism of piRNA generation and the functions of piRNA/PIWI in gastric, breast, kidney, colon, and lung cancers, providing a reference value for further piRNA research.

It is rapidly becoming evident that the formation of tumor-promoting pre-metastatic niches in secondary organs adds a previously unrecognized degree of complexity to the challenge of curing metastatic disease. Primary tumor cells orchestrate pre-metastatic niche formation through secretion of a variety of cytokines and growth factors that promote mobilization and recruitment of bone marrow-derived cells to future metastatic sites. Hypoxia within the primary tumor, and secretion of specific microvesicles termed exosomes, are emerging as important processes and vehicles for tumor-derived factors to modulate pre-metastatic sites. It has also come to light that reduced immune surveillance is a novel mechanism through which primary tumors create favorable niches in secondary organs. This review provides an overview of our current understanding of underlying mechanisms of pre-metastatic niche formation and highlights the common links as well as discrepancies between independent studies. Furthermore, the possible clinical implications, links to metastatic persistence and dormancy, and novel approaches for treatment of metastatic disease through reversal of pre-metastatic niche formation are identified and explored.