Special Issue Editorial

Cancer stem cells: Recent developments and future prospects

Phase III trials have shown improved survival in ovarian cancer patients when the anti-vascular endothelial growth factor (VEGF) therapy bevacizumab is added to first-line chemotherapy. However, further evidence is needed regarding bevacizumab when used with dose-dense paclitaxel/carboplatin chemotherapy in advanced ovarian cancer patients. This single-arm trial enrolled 184 advanced-stage (III–IV) epithelial ovarian cancer patients following primary debulking. Enrollees were treated with dose-dense paclitaxel/carboplatin chemotherapy with bevacizumab administered on the first day of cycles 2 through 6. Thereafter, maintenance bevacizumab was continued for 12 months in patients exhibiting persistent disease. The primary endpoint was the tumor response rate. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and adverse effects. VEGF-associated serum markers and VEGFA/B lymphoma Mo-MLV insertion region 1 homolog (BMI1) pathway proteins in tumor-derived ovarian epithelial cancer cells were analyzed. Of the enrollees with residual disease that completed at least four cycles, 56.6% had a complete response and 3.7% had a partial response. OS and PFS were significantly different between optimally debulked and suboptimally debulked patients (P < 0.05). The most common grade 3/4 adverse event was neutropenia. Patients with progressive disease showed greater basal serum VEGFA and ovarian VEGFA/BMI1 pathway protein expression relative to patients with stable disease and responsive disease (P < 0.05). In conclusion, bevacizumab plus dose-dense paclitaxel/carboplatin shows efficacy and tolerability in advanced ovarian cancer patients, especially in those having received optimal resection. Our evidence also suggests a prognostic relationship between serum VEGFA levels and a worse prognosis in ovarian cancer patients with measurable disease.

Tumor-initiating cells are important for the formation and maintenance of tumor bulks in various tumors. To identify surface markers of liver tumor-initiating cells, we performed primary tumorsphere culture and analyzed the expression of cluster of differentiation (CD) antigen genes using NanoString. Interestingly, we found significant upregulation of the complement proteins (p = 1.60 × 10⁻¹⁸), including C7 and CFH. Further studies revealed that C7 and CFH are required to maintain stemness in liver cancer cells. Knockdown of C7 and CFH expression abrogated tumorsphere formation and induced differentiation, whereas overexpression stimulated stemness factor expression as well as in vivo cell growth. Mechanistically, by studying C7 and CFH-dependent LSF-1 expression and its direct role on stemness factor transcription, we found that LSF-1 is involved in this regulation. Taken together, our data demonstrate the unprecedented role of complement proteins on the maintenance of stemness in liver tumor-initiating cells.

Chrysin, a naturally occurring flavone, abundantly found in numerous plant extracts including propolis and in honey is one of the most widely used herbal medicine in Asian countries. Nowadays, chrysin has become the foremost candidate exhibiting health benefits, owing to its multiple bioactivities such as antioxidant, anti-inflammatory, anti-allergic, anti-diabetic, anti-estrogenic, antibacterial and antitumor activities. Anticancer activity is most promising among the multiple pharmacological effects displayed by chrysin. In vitro and in vivo models have shown that chrysin inhibits cancer growth through induction of apoptosis, alteration of cell cycle and inhibition of angiogenesis, invasion and metastasis without causing any toxicity and undesirable side effects to normal cells. Chrysin displays these effects through selective modulation of multiple cell signaling pathways which are linked to inflammation, survival, growth, angiogenesis, invasion and metastasis of cancer cells. This broad spectrum of antitumor activity in conjunction with low toxicity underscores the translational value of chrysin in cancer therapy. The present review highlights the chemopreventive and therapeutic effects, molecular targets and antineoplastic mechanisms that contribute to the observed anticancer activity of chrysin.

Cancer chemoprevention is a strategy taken to block, reverse or retard the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal–preneoplasia–neoplasia–metastasis. Naturally occurring phytochemicals are becoming increasingly popular over synthetic drugs for several reasons, including safety, efficacy and easy availability. Nimbolide, a triterpene derived from the leaves and flowers of neem, is widely used in traditional medical practices for treating various human ailments. The neem limonoid exhibits multiple pharmacological effects among which its anticancer activity is the most promising. The preclinical and mechanistic studies carried over the decades have shown that nimbolide inhibits tumorigenesis and metastasis without any toxicity and unwanted side effects. Nimbolide exhibits anticancer activity through selective modulation of multiple cell signaling pathways linked to inflammation, survival, growth, invasion, angiogenesis and metastasis. The present review highlights the current knowledge on molecular targets that contribute to the observed anticancer activity of nimbolide related to (i) inhibition of carcinogenic activation and induction of antioxidant and carcinogen detoxification enzymes, (ii) induction of growth arrest and apoptosis; and (iii) suppression of proinflammatory signaling pathways related to cancer progression.

Pancreatic cancer (PC) is a deadly disease that is not amenable to any of the currently available treatment modalities. PC harbors a complex signaling that has both genetic and epigenetic origin. MicroRNAs (miRNAs) are short noncoding RNAs that are recognized to epigenetically modulate gene expression by weakly binding to the 3′ translated region of target mRNAs. A number of microRNAs have been recognized to be expressed aberrantly in PC. These findings have led researchers to aggressively pursue miRNAs for diagnostic and therapeutic markers in PC. Both identification and targeting of miRNAs is not straightforward, however, because each miRNA can modulate hundreds of different genes which in turn can influence an exponential number of different targets. In recent years, there has been a consensus that the complexity of miRNAs requires holistic approaches involving systems and computational components to tease out the specific target of each miRNA, which appear to be context dependent. This chapter comprehensively evaluates the importance of miRNAs in PC and how computational biology, particularly systems and network biology, can help prioritize miRNAs for diagnostic and therapeutic benefits.

Wilms tumor (WT) blastema retains gene expression profiles characteristic of the multipotent nephron progenitor pool, or cap mesenchyme (CM), in the developing kidney. As a result, WT blastema and the CM are believed to represent contextual analogues of one another. Sine oculis homeobox 2 (SIX2) is a transcription factor expressed specifically in the CM, provides a critical mechanism for CM self-renewal, and remains persistently active in WT blastema, although its purpose in this childhood malignancy remains unclear. We hypothesized that SIX2, analogous to its function in development, confers a survival pathway to blastema, the putative WT stem cell. To test its functional significance in WT biology, wild-type SIX2 was overexpressed in the human WT cell line, WiT49. After validating this model, SIX2 effects on anchorage-independent growth, proliferation, invasiveness, canonical WNT pathway signaling, and gene expression of specific WNT pathway participants were evaluated. Relative to controls, WiT49 cells overexpressing SIX2 showed significantly enhanced anchorage-independent growth and early-passage proliferation representing surrogates of cell survival. Interestingly, overexpression of SIX2 generally repressed TCF/LEF-dependent canonical WNT signaling, which activates and coordinates both differentiation and stem pathways, but significantly heightened canonical WNT signaling through the survivin promoter, a mechanism that exclusively maintains the stem state. In summary, when overexpressed in a human WT cell line, SIX2 enhances cell survival and appears to shift the balance in WNT/β-catenin signaling away from a differentiation path and toward a stem cell survival path.