Highlights of This Issue

Abstract

Lung cancer is one of the most prevalent and deadliest cancers worldwide. A major risk factor in the disease comes from the carcinogens produced from cigarette smoking. As such, understanding the cellular mechanisms of detoxification is of general interest. In the current study, mRNA expression analysis indicated that the detoxification enzyme glutathione S-transferase GST-M2 and connective tissue growth factor CCN2 (CTGF) were reduced in lung tumor tissue. Overexpression of GST-M2 increased CTGF expression, reduced cellular migration, and inhibited tumor growth and metastasis in animal models. Importantly, higher expression of GST-M2 and CCN2 using real-time PCR is associated with a favorable prognosis in non–small cell lung cancer (NSCLC). Overall, this study reveals the potential of GST-M2 as a novel tumor suppressor via inhibiting tumor growth and metastasis, which has been demonstrated in vitro and in animal models. The antitumor effects of GST-M2 and CCN2 activity in animal models have provoked an intense interest in the development of small-molecule activators of GST-M2 and CCN2 (and their gene therapy) to prevent NSCLCs in the future.As tumors grow, there is an increased demand for nutrients and oxygen. Therefore, intratumoral hypoxia is considered a major driving force in breast cancer progression and has been linked to metastasis. Gilkes and colleagues demonstrated that hypoxia-inducible factor 1 (HIF-1) mediated increased expression of collagen hydroxylases (PLOD1 and PLOD2), which modify type I collagen prior to its secretion into the extracellular matrix (ECM). In addition, human breast cancer specimens stratified by elevated PLOD2 expression were associated significantly with increased patient mortality. In animal models, PLOD2 knockdown resulted in a marked decrease in tumor stiffness, local tissue invasion, and metastasis to lymph nodes and lungs without affecting primary tumor growth. Taken together, HIF-1 stimulates PLOD2 expression and collagen biogenesis to promote metastasis of hypoxic breast cancer cells. Thus, specific inhibitors of HIF-1 and/or collagen hydroxylases may be of clinical benefit for preventing breast cancer metastasis.The primary treatment for advanced/metastatic prostate cancer involves androgen deprivation therapy. Unfortunately, recurrence develops due to reactivation of androgen receptor (AR) activity resulting in castration-resistance and frequent osteoblastic bone metastasis. Based on genomic analyses, Zheng and colleagues mechanistically identified WNT7B as a novel target of AR in castration-resistant prostate cancer (CRPC). Manipulation of WNT7B levels promoted CRPC cell growth under androgen-deprived conditions and activated a noncanonical WNT pathway involving protein kinase C (PKC) isozymes. Critically, WNT7B was selectively upregulated in human xenografts that induce an osteoblastic reaction when grown in bone. These results establish a connection between AR and WNT signaling and suggest a unique opportunity to develop effective therapies for advanced prostate cancer by targeting the AR-WNT7B-PKCs axis, which would inhibit CRPC growth and prevent the formation of a metastatic reservoir in bone.Considered a major driver of invasive solid tumor progression, epithelial-mesenchymal transformation (EMT) is a cellular reprogramming by which malignant epithelial cells generally lose their cell–cell adhesion properties to become highly invasive. Austin and colleagues used mesenchymally transformed breast cancer cells to demonstrate that the small molecule sarasinoside A1, at noncytotoxic doses, reversed a number of aspects of EMT. Sarasinoside A1 inhibited cell invasion and promoted cell adhesion in three-dimensional cultures. Interestingly, sarasinoside A1 also initiated a morphologic re-epithelialization and stabilized the cytoskeleton at sites of nascent cell–cell contact. Combined, these findings indicate the potential to impede tumor invasion and metastasis without the need to reinduce the expression of cell adhesion molecules, such as E-cadherin, that are often lost or silenced during mesenchymal transformation.