Choline phospholipid metabolism: A target in cancer cells?

The experience of treating cancer over the past several decades overwhelmingly demonstrates that the disease continues to evade the vast array of drugs and treatment modalities available in the twenty-first century. This is not surprising in view of the complexity of this disease, and the multiplicities of pathways available to the cancer cell to enable its survival. Although the progression of cancer arrives at a common end point of cachexia, organ failure, and death, common pathways are rare in cancer. Identifying and targeting common pathways that would act across these levels of multiplicity is essential for the successful treatment of this disease. Over the past decade, one common characteristic consistently revealed by magnetic resonance spectroscopic studies is the elevation of phosphocholine and total choline-containing compounds in cancer cells and solid tumors. This elevation has been observed in almost every single cancer type studied with NMR spectroscopy and can be used as an endogenous biomarker of cancer. In this article, we have summarized some of the observations on the choline phospholipid metabolism of cancer cells and tumors, and make a case for targeting the aberrant choline phospholipid metabolism of cancer cells.     

Airway imaging in disease: Gimmick or useful tool?

Airway remodeling is an important pathophysiological mechanism in a variety of chronic airway diseases. Historically investigators have had to use invasive techniques such as histological examination of excised tissue to study airway wall structure. The last several years has seen a proliferation of relatively noninvasive techniques to assess the airway branching pattern, wall thickness, and more recently, airway wall tissue components. These methods include computed tomography, magnetic resonance imaging, and optical coherence tomography. These new imaging technologies have become popular because to understand the physiology of lung disease it is important we understand the underlying anatomy. However, these new approaches are not standardized or available in all centers so a review of their validity and clinical utility is appropriate. This review documents how investigators are working hard to correct for inconsistencies between techniques so that they become more accepted and utilized in clinical settings. These new imaging techniques are very likely to play a frontline role in the study of lung disease and will, hopefully, allow clinicians and investigators to better understand disease pathogenesis and to design and assess new therapeutic interventions.     

CD9, a tetraspanin target for cancer therapy?

In the present minireview, we intend to provide a brief history of the field of CD9 involvement in oncogenesis and in the metastatic process of cancer, considering its potential value as a tumor-associated antigenic target. Over the years, CD9 has been identified as a favorable prognostic marker or predictor of metastatic potential depending on the cancer type. To understand its implications in cancer beside its use as an antigenic biomarker, it is essential to know its physiological functions, including its molecular partners in a given cell system. Moreover, the discovery that CD9 is one of the most specific and broadly expressed markers of extracellular membrane vesicles, nanometer-sized entities that are released into extracellular space and various physiological body fluids and play a role in intercellular communication under physiological and pathological conditions, notably the establishment of cancer metastases, has added a new dimension to our knowledge of CD9 function in cancer. Here, we will discuss these issues as well as the possible cancer therapeutic implications of CD9, their limitations, and pitfalls.     

Intraoperative imaging in ovarian cancer: fact or fiction?

Tumor-targeted fluorescence imaging for cancer diagnosis and treatment is an evolving field of research that is on the verge of clinical implementation. As each tumor has its unique biologic profile, selection of the most promising targets is essential. In this review, we focus on target finding in ovarian cancer, a disease in which fluorescence imaging may be of value in both adequate staging and in improving cytoreductive efforts, and as such may have a beneficial effect on prognosis. Thus far, tumor-targeted imaging for ovarian cancer has been applied only in animal models. For clinical implementation, the five most prominent targets were identified: folate receptor α, vascular endothelial growth factor, epidermal growth factor receptor, chemokine receptor 4, and matrix metalloproteinase. These targets were selected based on expression rates in ovarian cancer, availability of an antibody or substrate aimed at the target approved by the Food and Drug Administration, and the likelihood of translation to human use. The purpose of this review is to present requirements for intraoperative imaging and to discuss possible tumor-specific targets for ovarian cancer, prioritizing for targets with substrates ready for introduction into the clinic.     

Tumor-induced lymphangiogenesis: a target for cancer therapy?

Recent advances in understanding the biology of lymphangiogenesis, the new growth of lymphatic vessels, have cast new light on the molecular basis of metastasis to regional lymph nodes. The receptor tyrosine kinase VEGFR-3 is virtually exclusively expressed on lymphatic but not blood endothelium in the adult, and activation of VEGFR-3 by its ligands VEGF-C and VEGF-D is sufficient to induce lymphangiogenesis. Correlative studies with human tumors and functional studies using animal tumor models show that increased levels of VEGF-C or VEGF-D in tumors lead to enhanced numbers of lymphatic vessels in the vicinity of tumors, which in turn promotes metastasis to regional lymph nodes by providing a greater number of entry sites into the lymphatic system for invading tumor cells. These findings have prompted studies to investigate whether inhibitors of VEGFR-3 activation might represent novel therapeutic agents for the suppression of metastasis. However, a number of points regarding the therapeutic potential of anti-lymphangiogenic treatments in the context of cancer remain to be addressed. The spectrum and relative importance of molecules that induce lymphangiogenesis and the regulation of their expression during tumor progression, the reversibility of tumor-induced lymphangiogenesis, and possible side-effects of anti-lymphangiogenesis-based therapies all need to be investigated. Most importantly, the extent to which lymph node metastases contribute to the formation of metastases in other organs remains to be elucidated. These aspects are the focus of this review, and their investigation should serve as a roadmap to possible translational application.     

Can EGFR be a therapeutic target in breast cancer?

Epidermal growth factor receptor (EGFR) is highly expressed in certain cancer types and is involved in regulating the biological characteristics of cancer progression, including proliferation, metastasis, and drug resistance. Various medicines targeting EGFR have been developed and approved for several cancer types, such as lung and colon cancer. To date, however, EGFR inhibitors have not achieved satisfactory clinical results in breast cancer, which continues to be the most serious malignant tumor type in females. Therefore, clarifying the underlying mechanisms related to the ineffectiveness of EGFR inhibitors in breast cancer and developing new EGFR-targeted strategies (e.g., combination therapy) remain critical challenges. Various studies have demonstrated aberrant expression and maintenance of EGFR levels in breast cancer. In this review, we summarize the regulatory mechanisms underlying EGFR protein expression in breast cancer cells, including EGFR mutations, amplification, endocytic dysfunction, recycling acceleration, and degradation disorders. We also discuss potential therapeutic strategies that act directly or indirectly on EGFR, including reducing EGFR protein expression, treating the target protein to mediate precise clearance, and inhibiting non-EGFR signaling pathways. This review should provide new therapeutic perspectives for breast cancer patients with high EGFR expression.     

TGF-β, to target or not to target; to prevent thyroid cancer progression?

Thyroid cancer (TC) is a common endocrine cancer with a rising incidence. Current treatment fails to eliminate aggressive thyroid tumours, prompting an investigation into the processes that cause disease progression. In this review, we provide insight into TGF-β driven epithelial to mesenchymal transition (EMT), summarizing the current literature surrounding thyroid carcinogenesis, and discuss the potential for therapeutic strategies targeting the TGF-β signalling pathway. Understanding the underlying mechanisms that regulate cancer stem cell (CSC) growth and TGF-β signalling may provide novel therapeutic approaches for highly resistant TCs.     

CD93 in macrophages: A novel target for atherosclerotic plaque imaging?

Noninvasive imaging atherosclerotic (AS) plaque is of great importance for early diagnosis. Recently, CD93 in MΦ was linked to atherosclerosis development. Herein, we have investigated whether CD93 in MΦ is a potential novel target for atherosclerotic plaque imaging. CD93^hi and CD93^lo MΦ were prepared with or without LPS stimulation, before biological activity was evaluated. A rat AS model was produced with left carotid artery clamped. Whole‐body/ex vivo phosphor autoradiography of the artery and biodistribution were investigated after incorporation of ³H‐2‐DG into CD93^hi and CD93^lo MΦ or after ¹²⁵I‐α‐CD93 (¹²⁵I‐anti‐CD93mAb) injection. The plaque tissue was subjected to CD93/CD68 immunofluorescence/immunohistochemistry staining. CD93^hi and CD93^lo MΦ cells were successfully prepared without significant effect on bioactivity after incorporative labelled with ³H‐2‐DG. The AS model was successfully established. Biodistribution studies showed that adoptive transfer of ³H‐2‐DG‐CD93^hi MΦ or ¹²⁵I‐ α‐CD93 injection resulted in accumulation of radioactivity within the atherosclerotic plaque in the clamped left carotid artery. T/NT (target/non‐target, left/right carotid artery) ratio was higher in the ³H‐2‐DG‐CD93^hi MΦ adoptive transfer group than in the ³H‐2‐DG‐CD93^lo MΦ group (p < .05). Plaque radioactivity in the ¹²⁵I‐α‐CD93 injection group was significantly higher than in the ¹²⁵I‐IgG control group (p < .01). The higher radioactivity accumulated in the clamped left carotid artery was confirmed by phosphor autoradiography. More importantly, CD93/CD68 double‐positive MΦ accumulated at the atherosclerotic plaque in ³H‐2‐DG‐CD93^hi MΦ adoptive transfer group, which correlated with plaque radioactivity (r = .99, p < .01). In summary, both adoptive‐transferred ³H‐2‐DG‐labelled CD93^hi MΦ and ¹²⁵I‐α‐CD93 injection specifically targeted CD93 in atherosclerotic plaque. CD93 is a potential target in atherosclerotic plaque imaging.     

Gut microbiome in gastrointestinal cancer: a friend or foe?

The impact of the gut microbiome on host health is becoming increasingly recognized. To date, there is growing evidence that the complex characteristics of the microbial community play key roles as potential biomarkers and predictors of responses in cancer therapy. Many studies have shown that altered commensal bacteria lead to cancer susceptibility and progression in diverse pathways. In this review, we critically assess the data for gut microbiota related to gastrointestinal cancer, including esophageal, gastric, pancreatic, colorectal cancer, hepatocellular carcinoma and cholangiocarcinoma. Importantly, the underlying mechanisms of gut microbiota involved in cancer occurrence, prevention and treatment are elucidated. The purpose of this review is to provide novel insights for applying this understanding to the development of new therapeutic strategies in gastrointestinal cancer by targeting the microbial community.     

Therapeutics formulated to target cancer stem cells: Is it in our future?

With the political, social and financial drives for cancer research, many advances have been made in the treatment of many different cancer types. For example, given the increase in awareness, early detection, and treatment of breast and prostate cancers, we have seen substantial increases in survival rates. Unfortunately there are some realms of cancer that have not seen these substantial advancements, largely due to their rapid progression and the inability to specifically target therapy.