P-glycoprotein and cancer: what do we currently know?

Acquired resistance during cancer treatment is unfortunately a frequent event. There are several reasons for this, including the ability of the ATP-binding cassette transporters (ABC transporters), which are integral membrane proteins, to export chemotherapeutic molecules from the interior of the tumor cells. One important member of this family is the protein known as Permeability Glycoprotein (P-Glycoprotein, P-gp or ABCB1). Its clinical relevance relies mainly on the fact that the inhibition of P-gp and other ABC transporters could result in the reversal of the multidrug resistance (MDR) phenotype in some patients. Recently, other roles apart from being a key player in MDR, have emerged for P-gp. Therefore, this review discusses the relationship between P-gp and MDR, in addition to the possible role of this protein as a biomarker in cancer.

The genotypic and phenotypic impact of hypoxia microenvironment on glioblastoma cell lines.

BACKGROUND: Glioblastoma is a fatal brain tumour with a poor patient survival outcome. Hypoxia has been shown to reprogram cells towards a stem cell phenotype associated with self-renewal and drug resistance properties. Activation of hypoxia-inducible factors (HIFs) helps in cellular adaptation mechanisms under hypoxia. Similarly, miRNAs are known to be dysregulated in GBM have been shown to act as critical mediators of the hypoxic response and to regulate key processes involved in tumorigenesis. METHODS: Glioblastoma (GBM) cells were exposed to oxygen deprivation to mimic a tumour microenvironment and different cell aspects were analysed such as morphological changes and gene expression of miRNAs and survival genes known to be associated with tumorigenesis. RESULTS: It was observed that miR-128a-3p, miR-34-5p, miR-181a/b/c, were down-regulated in 6 GBM cell lines while miR-17-5p and miR-221-3p were upregulated when compared to a non-GBM control. When the same GBM cell lines were cultured under hypoxic microenvironment, a further 4-10-fold downregulation was observed for miR-34-5p, miR-128a-3p and 181a/b/c while a 3-6-fold upregulation was observed for miR-221-3p and 17-5p for most of the cells. Furthermore, there was an increased expression of SOX2 and Oct4, GLUT-1, VEGF, Bcl-2 and survivin, which are associated with a stem-like state, increased metabolism, altered angiogenesis and apoptotic escape, respectively. CONCLUSION: This study shows that by mimicking a tumour microenvironment, miRNAs are dysregulated, stemness factors are induced and alteration of the survival genes necessary for the cells to adapt to the micro-environmental factors occurs. Collectively, these results might contribute to GBM aggressiveness.

ABC transporters and the hallmarks of cancer: roles in cancer aggressiveness beyond multidrug resistance.

The ATP-binding cassette transporters (ABC transporters) have been intensely studied over the past 50 years for their involvement in the multidrug resistance (MDR) phenotype, especially in cancer. They are frequently overexpressed in both naive and post-treatment tumors, and hinder effective chemotherapy by reducing drug accumulation in cancer cells. In the last decade however, several studies have established that ABC transporters have additional, fundamental roles in tumor biology; there is strong evidence that these proteins are involved in transporting tumor-enhancing molecules and/or in protein-protein interactions that impact cancer aggressiveness, progression, and patient prognosis. This review highlights these studies in relation to some well-described cancer hallmarks, in an effort to re-emphasize the need for further investigation into the physiological functions of ABC transporters that are critical for tumor development. Unraveling these new roles offers an opportunity to define new strategies and targets for therapy, which would include endogenous substrates or signaling pathways that regulate these proteins.

MicroRNAs, Hypoxia and the Stem-Like State as Contributors to Cancer Aggressiveness.

MicroRNAs (miRNAs) are small non-coding RNA molecules that play key regulatory roles in cancer acting as both oncogenes and tumor suppressors. Due to their potential roles in improving cancer prognostic, predictive, diagnostic and therapeutic approaches, they have become an area of intense research focus in recent years. Several studies have demonstrated an altered expression of several miRNAs under hypoxic condition and even shown that the hypoxic microenvironment drives the selection of a more aggressive cancer cell population through cellular adaptations referred as the cancer stem-like cell. These minor fractions of cells are characterized by their self-renewal abilities and their ability to maintain the tumor mass, suggesting their crucial roles in cancer development. This review aims to highlight the interconnected role between miRNAs, hypoxia and the stem-like state in contributing to the cancer aggressiveness as opposed to their independent contributions, and it is based in four aggressive tumors, namely glioblastoma, cervical, prostate, and breast cancers.

Glioblastoma Therapy in the Age of Molecular Medicine.

Glioblastoma (GBM) is the most common and fatal primary malignant brain tumor. Despite advances in the understanding of the biology of gliomas, little has changed in the treatment of these tumors in the past decade. Phase III clinical trials showed no benefit for the use of bevacizumab in newly diagnosed patients, leading to a renewed search for new antiangiogenic drugs, as well as immunotherapeutic approaches, including checkpoint inhibitors, chimeric antigen receptor T cells, and intracerebral CpG-oligodeoxynucleotides. The emerging role of infiltrating microglia and macrophages, and of metabolic alterations, is also being taken into account in preclinical research and drug development. In this review, we discuss progress in the search for new therapeutic strategies, particularly approaches focusing on the tumor microenvironment.

GBM-Derived Wnt3a Induces M2-Like Phenotype in Microglial Cells Through Wnt/ß-Catenin Signaling.

Glioblastoma is an extremely aggressive and deadly brain tumor known for its striking cellular heterogeneity and capability to communicate with microenvironment components, such as microglia. Microglia-glioblastoma interaction contributes to an increase in tumor invasiveness, and Wnt signaling pathway is one of the main cascades related to tumor progression through changes in cell migration and invasion. However, very little is known about the role of canonical Wnt signaling during microglia-glioblastoma crosstalk. Here, we show for the first time that Wnt3a is one of the factors that regulate interactions between microglia and glioblastoma cells. Wnt3a activates the Wnt/ß-catenin signaling of both glioblastoma and microglial cells. Glioblastoma-conditioned medium not only induces nuclear translocation of microglial ß-catenin but also increases microglia viability and proliferation as well as Wnt3a, cyclin-D1, and c-myc expression. Moreover, glioblastoma-derived Wnt3a increases microglial ARG-1 and STI1 expression, followed by an upregulation of IL-10 mRNA levels, and a decrease in IL1ß gene expression. The presence of Wnt3a in microglia-glioblastoma co-cultures increases the formation of membrane nanotubes accompanied by changes in migration capability. In vivo, tumors formed from Wnt3a-stimulated glioblastoma cells presented greater microglial infiltration and more aggressive characteristics such as growth rate than untreated tumors. Thus, we propose that Wnt3a belongs to the arsenal of factors capable of stimulating the induction of M2-like phenotype on microglial cells, which contributes to the poor prognostic of glioblastoma, reinforcing that Wnt/ß-catenin pathway can be a potential therapeutic target to attenuate glioblastoma progression.

Microglia/Astrocytes-Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors.

In recent years, the functions of glial cells, namely, astrocytes and microglia, have gained prominence in several diseases of the central nervous system, especially in glioblastoma (GB), the most malignant primary brain tumor that leads to poor clinical outcomes. Studies showed that microglial cells or astrocytes play a critical role in promoting GB growth. Based on the recent findings, the complex network of the interaction between microglial/astrocytes cells and GB may constitute a potential therapeutic target to overcome tumor malignancy. In the present review, we summarize the most important mechanisms and functions of the molecular factors involved in the microglia or astrocytes-GB interactions, which is particularly the alterations that occur in the cell's extracellular matrix and the cytoskeleton. We overview the cytokines, chemokines, neurotrophic, morphogenic, metabolic factors, and non-coding RNAs actions crucial to these interactions. We have also discussed the most recent studies regarding the mechanisms of transportation and communication between microglial/astrocytes - GB cells, namely through the ABC transporters or by extracellular vesicles. Lastly, we highlight the therapeutic challenges and improvements regarding the crosstalk between these glial cells and GB.

Cancer in Kenya: types and infection-attributable. Data from the adult population of two National referral hospitals (2008-2012).

Background: Cancer in Africa is an emerging health problem. In Kenya it ranks third as a cause of death after infectious and cardiovascular diseases. Approximately 15% of the global cancer burden is attributable to infectious agents, with higher percentages in developing countries. Therefore, this study aimed to provide comprehensive hospital based data to inform policies Method: A retrospective survey was conducted at Kenyatta National Hospital (KNH) and Moi Teaching and Referral Hospital (MTRH) from 2008 to 2012.  Data was obtained from the patients files using a pre-designed data collection form. The study was approved by the KNH/University of Nairobi and MTRH Ethics and Research Committees. Results: In KNH, the five most common cancers in females (n=300) were cervical 62 (20.7%), breast 59 (19.7%), ovarian 22 (7.3%), chronic leukemia 16 (5.3%), endometrial and gastric both with 15 (5%). In males (n=200) they were prostate 23 (11.5%), laryngeal 19 (9.5%), colorectal 17 (8.5%), esophageal 14 (7.0%) and nasopharyngeal carcinoma 12 (6%). The top infection-attributable cancers were: cervical 62 (12.4%), colorectal 31 (6.2%), gastric 26 (5.2%), prostate 23 (4.6%) and nasopharyngeal carcinoma 17 (3.4%). In contrast, in MTRH the five most common cancers in females (n=282) were breast cancer 74 (26.2%), cervical 41 (14.5%), Kaposi's sarcoma 38 (13.5%), non-Hodgkin's lymphoma 15(5.3%) and ovarian 14 (5%) while in males (n=218) they were Kaposi's sarcoma 55 (25.2%), non-Hodgkin's lymphoma 22 (10.1%),  chronic leukemia 17 (7.8%), colorectal and esophageal cancers both with 16 (7.3%). The top infection-attributable cancers were: Kaposi's sarcoma 93 (18.6%), cervical 41 (8.2%), non-Hodgkin's lymphoma 37 (7.4%), colorectal 27 (5.4%) and liver cancer 16 (3.2%). Conclusion: This study presents a picture of the burden of cancer and infection-attributable cancer from two referral hospitals in Kenya. Reducing the burden of infection-attributable cancers can translate to a reduction of the overall cancer burden.