BBA - Reviews on Cancer (v.1806, #2)

Antiangiogenic drugs are now intensively used in clinical oncology, but some drawbacks still hamper their development. First, it is frequently unclear what patient subpopulation is likely to gain clinical benefit from these expensive therapies; second, there is evidence of (sometimes rapid) development of drug resistance in many patients; third, the results of some preclinical and clinical studies have suggested acceleration of malignant cell aggressiveness when some antiangiogenic therapies are terminated. Here we discuss the role of soluble molecules and cellular markers of neoplastic angiogenesis for patient selection and follow-up during treatment. These markers should help clinicians to decide the right therapy, advise them of the generation of mechanisms of drug resistance during antiangiogenic treatment, and finally suggest the most appropriate next line of therapy according to the new patterns of cancer vascularization induced by antiangiogenic therapies.
Keywords: Angiogenesis; Oncology endothelial cells; Endothelial progenitors;

Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma by Nikki P. Lee; Ronnie T.P. Poon; Felix H. Shek; Irene O.L. Ng; John M. Luk (138-145).
Cadherin is an important cell adhesion molecule that plays paramount roles in organ development and the maintenance of tissue integrity. Dysregulation of cadherin expression is often associated with disease pathology including tissue dysplasia, tumor formation, and metastasis. Cadherin-17 (CDH17), belonging to a subclass of 7D-cadherin superfamily, is present in fetal liver and gastrointestinal tract during embryogenesis, but the gene becomes silenced in healthy adult liver and stomach tissues. It functions as a peptide transporter and a cell adhesion molecule to maintain tissue integrity in epithelia. However, recent findings from our group and others have reported aberrant expression of CDH17 in major gastrointestinal malignancies including hepatocellular carcinoma (HCC), stomach and colorectal cancers, and its clinical association with tumor metastasis and advanced tumor stages. Furthermore, alternative splice isoforms and genetic polymorphisms of CDH17 gene have been identified in HCC and linked to an increased risk of HCC. CDH17 is an attractive target for HCC therapy. Targeting CDH17 in HCC can inhibit tumor growth and inactivate Wnt signaling pathway in concomitance with activation of tumor suppressor genes. Further investigation on CDH17-mediated oncogenic signaling and cognate molecular mechanisms would shed light on new targeting therapy on HCC and potentially other gastrointestinal malignancies.
Keywords: Cadherin-17; Oncogene; Wnt signaling; Biomarker; Therapeutic target;

Tumors of the oral cavity provide an ideal model to study various stages of epithelial tumor progression. A group of cancer cells termed cancer stem cells (CSCs) eludes therapy, persists and initiates recurrence augmenting malignant spread of the disease. Hitherto, accurate identification and separation of such minimal residual cells have proven futile due to lack of identifiable traits to single out these cells from the heterogeneous tumor bulk. In this review we have compiled comprehensive evidence from comparative phenotypic and genotypic studies on normal oral mucosa as well as tumors of different grades to elucidate that differential expression patterns of putative stem cells markers may identify ‘minimal residual disease’ in oral squamous cell carcinoma. We propose the “cancer stem cell shift hypothesis” to explain the exact identity and switch-over, tumor-promoting mechanisms adapted by putative CSCs with correlation to tumor staging.
Keywords: Oral squamous cell carcinoma (OSCC); Minimal residual disease (MRD); Cancer stem cell (CSC); Multidrug resistance (MDR); Side population (SP);

Implications of cancer-associated systemic inflammation for biomarker studies by Magdalena Kowalewska; Radoslawa Nowak; Magdalena Chechlinska (163-171).
Highly sensitive molecular technologies provide new capacities for cancer biomarker research, but with sensitivity improvements marker specificity is significantly decreased, and too many false-positive results should disqualify the measurement from clinical use. Hence, of the thousands of potential cancer biomarkers only a few have found their way to clinical application. Differentiating false-positive results from true-positive (cancer-specific) results can indeed be difficult, if validation of a marker is performed against inadequate controls.We present examples of accumulating evidence that not only local but also systemic inflammatory reactions are implicated in cancer development and progression and interfere with the molecular image of cancer disease. We analyze several modern strategies of tumor marker discovery, namely, proteomics, metabonomics, studies on circulating tumor cells and circulating free nucleic acids, or their methylation degree, and provide examples of scarce, methodologically correct biomarker studies as opposed to numerous methodologically flawed biomarker studies, that examine cancer patients' samples against those of healthy, inflammation-free persons and present many inflammation-related biomarker alterations in cancer patients as cancer-specific. Inflammation as a cancer-associated condition should always be considered in cancer biomarker studies, and biomarkers should be validated against their expression in inflammatory conditions.
Keywords: Cancer biomarker; Marker specificity; Marker validation; Inflammation; CTC;

Cisplatin resistance: Preclinical findings and clinical implications by Beate Köberle; Maja T. Tomicic; Svetlana Usanova; Bernd Kaina (172-182).
Cisplatin is used for the treatment of many types of solid cancers. While testicular cancers respond remarkably well to cisplatin, the therapeutic efficacy of cisplatin for other solid cancers is limited because of intrinsic or acquired drug resistance. Our understanding about the mechanisms underlying cisplatin resistance has largely arisen from studies carried out with cancer cell lines in vitro. The process of cisplatin resistance appears to be multifactorial and includes changes in drug transport leading to decreased drug accumulation, increased drug detoxification, changes in DNA repair and damage bypass and/or alterations in the apoptotic cell death pathways. Translation of these preclinical findings to the clinic is emerging, but still scarce. The present review describes and discusses the clinical relevance of in vitro models by comparing the preclinical findings to data obtained in clinical studies.
Keywords: Cancer; Cisplatin; Drug resistance; DNA damage repair; DNA damage bypass; DNA damage response;

Protein kinase D as a potential new target for cancer therapy by Courtney R. LaValle; Kara M. George; Elizabeth R. Sharlow; John S. Lazo; Peter Wipf; Q. Jane Wang (183-192).
Protein kinase D is a novel family of serine/threonine kinases and diacylglycerol receptors that belongs to the calcium/calmodulin-dependent kinase superfamily. Evidence has established that specific PKD isoforms are dysregulated in several cancer types, and PKD involvement has been documented in a variety of cellular processes important to cancer development, including cell growth, apoptosis, motility, and angiogenesis. In light of this, there has been a recent surge in the development of novel chemical inhibitors of PKD. This review focuses on the potential of PKD as a chemotherapeutic target in cancer treatment and highlights important recent advances in the development of PKD inhibitors.
Keywords: Protein kinase D; Cancer; Small molecule inhibitors;

Crosstalk and DC-SCRIPT: Expanding nuclear receptor modulation by M. Ansems; S. Hontelez; N. Karthaus; P.N. Span; G.J. Adema (193-199).
Nuclear receptors (NR) are intracellular receptors that execute a transcriptional program upon binding to hormones, vitamins and metabolic products. They are key regulators of distinct physiological processes, including growth and differentiation, metabolism, and immunity. The impact of NR activation on a given cell can differ from proliferation induction to programmed cell death. NR malfunction is associated with different diseases, such as diabetes, chronic inflammatory diseases and cancer. Much progress has been made towards understanding the transcriptional regulation by individual NR at the molecular level. However, essentially every cell expresses multiple NR and will encounter complex mixtures of NR ligands during its life cycle. In this review, we will focus on novel insights in balancing NR activity via NR crosstalk and DC-SCRIPT/ZNF366, a bi-functional NR coregulator. The impact on breast cancer development and prognosis will be discussed.
Keywords: DC-SCRIPT/ZNF366; Breast cancer; Crosstalk; Retinoic acid receptor; Estrogen receptor;

Serum microRNAs as powerful cancer biomarkers by Jürgen Wittmann; Hans-Martin Jäck (200-207).
MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level by either degrading or blocking translation of messenger RNA targets. Recent expression profiling studies have revealed that miRNAs play important regulatory roles in a variety of cellular functions as well as in every cancer type studied so far. Lately, the discovery of miRNAs in the serum of cancer patients opened up the exciting prospective of using miRNAs as powerful and non-invasive cancer biomarkers. In this article, we review the current literature on serum miRNAs in different cancer types and the approaches used to detect and quantify these molecules. We then discuss the potential of miRNA biomarkers to improve disease diagnosis by distinguishing healthy from malignant tissues, identifying the tissue of origin in poorly differentiated tumors or tumors of unknown origin and distinguishing between different subtypes of the same tumor. We will also compare the advantages and disadvantages of potential serum miRNA biomarker molecules for cancer classification, estimation of prognosis and prediction of therapeutic efficacy. Finally, we will establish a set of criteria that these new molecules and clinical studies that use them must fulfill before they can be used as reliable tools in diagnostic and prognostic settings.
Keywords: MicroRNA; Serum; Biomarker; Exosome; Cancer;

The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas by Karène Mahtouk; Esther P.M. Tjin; Marcel Spaargaren; Steven T. Pals (208-219).
Hepatocyte growth factor (HGF) and its receptor MET are essential during embryonic development and throughout postnatal life. However, aberrant MET activation, due to overexpression, mutations, or autocrine ligand production, contributes to the development and progression of a variety of human cancers, often being associated with poor clinical outcome and drug resistance. B cell malignancies arise from B cells that are clonally expanded at different stages of differentiation. Despite major therapeutic advances, most mature B cell malignancies remain incurable and biologically-oriented therapeutic strategies are urgently needed. This review addresses the role of the HGF/MET pathway during B cell development and discusses how its aberrant activation contributes to the development of B cell lymphoproliferative disorders, with particular emphasis on multiple myeloma and diffuse large B cell lymphoma. These insights, combined with the recent development of clinical-grade agents targeting the MET pathway, provide the rationale to envision the HGF/MET pathway as a new promising target for the treatment of B cell malignancies.
Keywords: HGF; MET; B cell lymphoproliferative disorder; Multiple myeloma; Diffuse large B cell lymphoma;

Autophagy is a therapeutic target in anticancer drug resistance by Suning Chen; Sumaiyah K. Rehman; Wei Zhang; Aidong Wen; Libo Yao; Jian Zhang (220-229).
Autophagy is a type of cellular catabolic degradation response to nutrient starvation or metabolic stress. The main function of autophagy is to maintain intracellular metabolic homeostasis through degradation of unfolded or aggregated proteins and organelles. Although autophagic regulation is a complicated process, solid evidence demonstrates that the PI3K-Akt-mTOR, LKB1-AMPK-mTOR and p53 are the main upstream regulators of the autophagic pathway. Currently, there is a bulk of data indicating the important function of autophagy in cancer. It is noteworthy that autophagy facilitates the cancer cells' resistance to chemotherapy and radiation treatment. The abrogation of autophagy potentiates the re-sensitization of therapeutic resistant cancer cells to the anticancer treatment via autophagy inhibitors, such as 3-MA, CQ and BA, or knockdown of the autophagy related molecules. In this review, we summarize the accumulation of evidence for autophagy's involvement in mediating resistance of cancer cells to anticancer therapy and suggest that autophagy might be a potential therapeutic target in anticancer drug resistance in the future.
Keywords: Autophagy; Cancer; Drug resistance;

The Aurora-A/TPX2 complex: A novel oncogenic holoenzyme? by Italia Anna Asteriti; Wilhelmina Maria Rensen; Catherine Lindon; Patrizia Lavia; Giulia Guarguaglini (230-239).
The Aurora-A kinase regulates cell division by phosphorylating multiple downstream targets in the mitotic apparatus. Aurora-A is frequently overexpressed in tumor cells and it is therefore regarded as a novel candidate target in anti-cancer therapy. Its actual contribution to cell transformation, however, is not entirely clarified; furthermore, its transforming ability has been found to vary broadly depending on the systems and experimental conditions in which it was assayed. This variability suggests that Aurora-A overexpression requires the concomitant deregulation of partner factor(s) to fully elicit its oncogenic potential. Molecular and structural studies indicate that the full activation and correct mitotic localisation of Aurora-A require its interaction with the spindle regulator TPX2. In this review we propose a brief reappraisal of Aurora-A intrinsic oncogenic features. We then present literature screening data indicating that TPX2 is also overexpressed in many tumor types, and, furthermore, that Aurora-A and TPX2 are frequently co-overexpressed. We therefore propose that the association of Aurora-A and TPX2 gives rise to a novel functional unit with oncogenic properties. We also suggest that some of the roles that are conventionally attributed to Aurora-A in cell transformation and tumorigenesis could in fact be a consequence of the oncogenic activation of this unit.
Keywords: Aurora-A; TPX2; Cancer;

Camptothecin is a selective inhibitor of DNA topoisomerase I, and has effective antitumor activity. Recently, camptothecin has been shown to activate the transcription of low-abundance antisense RNAs at the HIF-1α gene locus in human cancer cells in a Topoisomerase I-dependent manner. The activation of antisense transcription is likely due to sustained drug interference with transcription regulation mechanisms leading to a more open chromatin conformation and de-repression/activation of antisense transcription. Camptothecin readily inhibits Topoisomerase I in cells, and the enzyme inhibition activates transcriptional Cdk (Cdk9 and/or Cdk7) activity leading to the hyperphosphorylation of the CTD of the largest subunit of RNA polymerase II (RNAP II). This results in an alteration of RNAP II regulation with specific effects at transcription levels. Thus, the findings have documented that camptothecin can interfere with specific transcription regulatory steps, impairing the balance of cellular antisense and sense transcripts at the HIF-1α gene locus. That may have a considerable impact on cancer therapy development particularly for non-responsive human tumors.
Keywords: Camptothecin; Topoisomerase I; RNA polymerase; Transcription pausing; HIF1a;

Validating cancer drug targets through chemical genetics by Mark E. Burkard; Prasad V. Jallepalli (251-257).
Targeted therapies for cancer promise to revolutionize treatment by specifically inactivating pathways needed for the growth of tumor cells. The most prominent example of such therapy is imatinib (Gleevec), which targets the BCR–ABL kinase and provides an effective low-toxicity treatment for chronic myelogenous leukemia. This success has spawned myriad efforts to develop similarly targeted drugs for other cancers. Unfortunately, the high expectations of these efforts have not yet been realized, likely due to the genetic diversity among and within tumors, as well as the complex and largely unpredictable interactions of drug-like compounds with innumerable targets that affect cellular and organismal metabolism. While improvements in sequencing technologies are beginning to address the first problem, solving the second problem requires methods for linking specific features of the cancer genome to their optimally targeted therapies. One approach, referred to as chemical genetics, accomplishes this by genetic control of chemical susceptibility. Chemical genetics is a crucial tool for the rational development of cancer drugs.
Keywords: Kinase; Inhibitor; Neoplasm; Resistance; Mutagenesis;

Targeting Notch signaling pathway to overcome drug resistance for cancer therapy by Zhiwei Wang; Yiwei Li; Aamir Ahmad; Asfar S. Azmi; Sanjeev Banerjee; Dejuan Kong; Fazlul H. Sarkar (258-267).
Chemotherapy is an important therapeutic strategy for cancer treatment and remains the mainstay for the management of human malignancies; however, chemotherapy fails to eliminate all tumor cells because of intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Recently, emerging evidences suggest that Notch signaling pathway is one of the most important signaling pathways in drug-resistant tumor cells. Moreover, down-regulation of Notch pathway could induce drug sensitivity, leading to increased inhibition of cancer cell growth, invasion, and metastasis. This article will provide a brief overview of the published evidences in support of the roles of Notch in drug resistance and will further summarize how targeting Notch by “natural agents” could become a novel and safer approach for the improvement of tumor treatment by overcoming drug resistance.
Keywords: Notch; Drug resistance; Cancer; EMT;

TBX2 and TBX3: The special value for anticancer drug targets by Juan Lu; Xiang-Ping Li; Qi Dong; Hsiang-fu Kung; Ming-Liang He (268-274).
TBX2 and TBX3 are members of the T-box family of transcription factors, which are implicated in embryonic development. Unlike most members of the T-box family, TBX2 and TBX3 are the only mammalian T-box factors which function as transcriptional repressors, mediated by the repression domain in the C-terminal. In addition to a role in development, recent evidence suggests that TBX2 and TBX3 are overexpressed in a number of cancers, including melanoma, breast, liver, lung, pancreas, ovarian, and cervical cancers. However, there is little information about the mechanisms for how these T-box genes contribute to tumorigenesis. Upregulation of TBX2 and TBX3 suppresses the expression of p14ARF and p21CIP1 and promotes bypass of senescence through inactivation of p53 pathway. TBX2 functionally interacts with pRb, and pRb modulates TBX2 functional specificity. In addition, TBX2 is a player of Wnt signaling while TBX3 is a downstream target of the Wnt/beta-catenin pathway, and overexpression of TBX2 and TBX3 represses the expression of E-cadherin, which is demonstrated to be a prerequisite for epithelial tumor cell invasion. Moreover, TBX2 is shown to interact with EGR1 to block multiple downstream tumor suppressors. Here, we review the current knowledge on TBX2 and TBX3 in tumorigenesis and prospect their special value for development of target-based anticancer drugs.
Keywords: TBX2; TBX3; Tumorigenesis;

The translational regulator eIF3a: The tricky eIF3 subunit! by Federica Saletta; Yohan Suryo Rahmanto; Des R. Richardson (275-286).
Regulation of gene expression is a fundamental step in cellular physiology as abnormalities in this process may lead to de-regulated growth and cancer. Translation of mRNA is mainly regulated at the rate-limiting initiation step, where many eukaryotic initiation factors (eIFs) are involved. The largest and most complex initiation factor is eIF3 which plays a role in translational regulation, cell growth and cancer. The largest subunit of eIF3 is eIF3a, although it is not required for the general function of eIF3 in translation initiation. However, eIF3a may play a role as a regulator of a subset of mRNAs and has been demonstrated to regulate the expression of p27kip1, tyrosinated α-tubulin and ribonucleotide reductase M2 subunit. These molecules have a pivotal role in the regulation of the cell cycle. Moreover, the eIF3a mRNA is ubiquitously expressed in all tissues at different levels and is found elevated in a number of cancer types. eIF3a can modulate the cell cycle and may be a translational regulator for proteins important for entrance into S phase. The expression of eIF3a is decreased in differentiated cells in culture and the suppression of eIF3a expression can reverse the malignant phenotype and change the sensitivity of cells to cell cycle modulators. However, the role of eIF3a in cancer is still unclear. In fact, some studies have identified eIF3a to be involved in cancer development, while other results indicate that it could provide protection against evolution into higher malignancy. Together, these findings highlight the “tricky” and interesting nature of eIF3a.
Keywords: Translation; Eukaryotic initiation factors; Cell cycle; Differentiation;

Reversible phosphorylation in haematological malignancies: Potential role for protein tyrosine phosphatases in treatment? by Roberta R. Ruela-de-Sousa; Karla C.S. Queiroz; Maikel P. Peppelenbosch; Gwenny M. Fuhler (287-303).
Most aspects of leukocyte physiology are under the control of reversible tyrosine phosphorylation. It is clear that excessive phosphorylation of signal transduction elements is a pivotal element of many different pathologies including haematological malignancies and accordingly, strategies that target such phosphorylation have clinically been proven highly successful for treatment of multiple types of leukemias and lymphomas. Cellular phosphorylation status is dependent on the resultant activity of kinases and phosphatases. The cell biology of the former is now well understood; for most cellular phosphoproteins we now know the kinases responsible for their phosphorylation and we understand the principles of their aberrant activity in disease. With respect to phosphatases, however, our knowledge is much patchier. Although the sequences of whole genomes allow us to identify phosphatases using in silico methodology, whereas transcription profiling allows us to understand how phosphatase expression is regulated during disease, most functional questions as to substrate specificity, dynamic regulation of phosphatase activity and potential for therapeutic intervention are still to a large degree open. Nevertheless, recent studies have allowed us to make meaningful statements on the role of tyrosine phosphatase activity in the three major signaling pathways that are commonly affected in leukemias, i.e. the Ras–Raf–ERK1/2, the Jak–STAT and the PI3K–PKB–mTOR pathways. Lessons learned from these pathways may well be applicable elsewhere in leukocyte biology as well.
Keywords: Protein tyrosine phosphatases; Lipid phosphatase; Signal transduction; Haematological malignancies;