Current Cancer Drug Targets - Volume 15, Issue 2, 2015

Mesenchymal stem/stromal cells (MSCs) are known to be the helpers for the healing of tissue damage, often referred to as ambulatory cells. However, MSCs are also recruited by cancer cells to similarly aid in tumor growth and progression. In this review, some of the key steps in cancer progression and metastases are described including the various steps in which MSCs participate and may play important roles. MSCs aid in cancer cells’ ability to evade immune attack, while promoting tumor angiogenesis, even being counter-acting against chemotherapeutics and other drugs used to fight various cancers. Furthermore, MSCs participate in many of the crucial steps in invasion and metastasis, including stimulating the epithelial-mesenchymal transition (EMT) and induction of stem-like properties that allow cancer stem cells to increase their survivability through the circulation. These steps are described in detail. Differences between circulating tumor cells (CTCs) and cancer stem cells (CSCs) are discussed, along with descriptions of the formation of a pre-metastatic niche, the role of exosomes from both cancer cells and MSCs in metastasis and tumor reseeding (self-seeding). More and more, MSCs are being proposed as a promising tumor targeting drug-delivery tool. In order to fulfill this promise, further understanding of the precise roles that MSCs play in the process of cancer metastases must be achieved, in attempting to create remedies that will improve the outcome of available therapeutics.

Deregulated c-MYC (hereafter MYC) is widely expressed in many human tumors. Myctransgenic mouse models produce diverse tumors. MYC is a strong driver of tumorigenesis and is required for tumor maintenance. MYC is therefore an attractive target for cancer treatment. However, genetic and pharmacological approaches for the targeted inactivation of MYC for the treatment of MYC-overexpressing tumors have been shown to be unsatisfactory. MYC expression is regulated by different mechanisms at transcriptional, post-transcriptional, and post-translational levels. Turnover of MYC protein is an important step that influences the expression and function of MYC. MYC turnover is predominantly controlled by the GSK3/FBW7 axis that is regulated by multiple elements. Small molecule inhibitors (SMIs) can influence the stability and activity of MYC protein by targeting the axis and its regulator elements. Wang et al. (2004) first introduced the concept of MYC-mediated synthetic lethality (MYC-SL) induced by TRAIL and DR5-agonists. Researchers have turned to synthetic lethality as a treatment strategy for MYC-overexpressing tumors. MYC function is closely associated with MYC levels. Two strategies have been developed to treat MYC-overexpressing tumors by upregulating or downregulating MYC. An SMI can induce MYC-SL by increasing MYC expression through the inactivation of the GSK3β/FBW7 axis and CK1. Elevated MYC levels lead to DNA damage, senescence, and apoptosis. An SMI can also induce MYC-SL by decreasing MYC expression through the activation of the GSK3β/FBW7 axis, the inactivation of PP2A inhibitors, and the inhibition of ARK5, AUK-A, Brd4, CDK1, CDK2, CHK1, and SAE1/2. Reduced MYC levels cause tumor regression. Some SMIs have entered phase I and II clinical trials. SMIs may be used in the near future to treat cancers co-overexpressing MYC and the corresponding MYC-SL genes.

Breast cancer is one of the most common malignancies among women, representing nearly 30% of newly diagnosed cancers every year. Till date, various therapeutic interventions, including surgery, chemotherapy, hormonal therapy, and radiotherapy are available and are known to cause a significant decline in the overall mortality rate. However, therapeutic resistance, recurrence and lack of treatment in metastasis are the major challenges that need to be addressed. Increasing evidence suggests the presence of cancer stem cells (CSCs) in heterogeneous population of breast tumors capable of selfrenewal and differentiation and is considered to be responsible for drug resistance and recurrence. Therefore, compound that can target both differentiated cancer cells, as well as CSCs, may provide a better treatment strategy. Due to safe nature of dietary agents and health products, investigators are introducing them into clinical trials in place of chemotherapeutic agents.This current review focuses on phytochemicals, mainly flavonoids that are in use for breast cancer therapy in preclinical phase. As phytochemicals have several advantages in breast cancer and cancer stem cells, new synthetic series for breast cancer therapy from analogues of most potent natural molecule can be developed via rational drug design approach.

Glioblastoma (grade IV astrocytoma) is an aggressive and incurable form of brain tumor. It invariably shows extensive invasion at the time of diagnosis, often involving both hemispheres. Recent studies have given us a very detailed picture of glioblastoma genetics. These paint a picture of a disease with extensive heterogeneity, both between patients and within individual patients. This within patient heterogeneity presents a major challenge in the design of targeted therapies. One approach is to identify targets that are common downstream elements in signaling pathways that are aberrantly activated in glioblastoma. Here we review the evidence that the atypical protein kinase C family member PKCι may fulfill this role. Our current understanding of PKCι activation mechanisms is discussed and related to common genetic changes in glioblastoma. The data showing an essential role for PKCι in multiple aspects of glioblastoma pathology are also reviewed. Finally, data on the role of PKCι in normal brain function are reviewed for insights into potential side effects of PKCι inhibition in the central nervous system.

Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications. Recent studies reveal a proliferative role of YY1 in oncogenesis. Consistently, YY1 overexpression has been observed in various human malignancies and its levels correlate with poor prognoses of many types of cancers. In this review, we focus on the signaling pathways and regulatory proteins that YY1 modulates to promote tumor cell growth, proliferation, migration and metastasis. We also discuss the signals and molecules that regulate YY1 expression and function in cancer-related context. Based on the expression feature and regulatory activities in tumor cells, YY1 possesses a great potential as a biomarker for many cancers and can serve as a therapeutic target clinically to impede cancer development and progression or sensitize cancer cells to anticancer drugs.

The signal transduction pathway initiated by vascular endothelial growth factor-vascular endothelial growth factor receptor 2 (VEGF-VEGFR2) plays an important role in the angiogenesis of tumors. The effective antagonists of VEGFR2 would behave as potent drugs for the treatment of malignant cancers. In our study, specific binding peptides with high affinity to VEGFR2 were obtained through bacterial display technology. Conserved motif (FF/YEXWGVK) among those peptide sequences was discovered. One of the selected peptides, VRBP1 (YDGNSFYEMWGVKPASES) was identified by screening the biased bacterial peptide library and its physiochemical feature was further characterized. The results of surface plasmon resonance (SPR) assay indicated that the dissociation constant (KD) value of VRBP1 was 228.3 nM and this peptide competed with VEGF binding to VEGFR2. Particles conjugated with VRBP1 could recognize the human umbilical vein endothelial cells (HUVEC) which express VEGFR2 on the surface. Further therapeutic effect of VRBP1 was examined by in vivo experiments. VRBP1 could result in a significant decrease in tumor size of H460 xenografts. The results from the immunohistochemical assay showed that CD31 positive signals in VRBP1-treated group were fewer than those in the control ones. These data highlighted the potential of VEGFR2-binding peptides as effective molecules for cancer diagnosis and therapy.