Cancer Biomarkers - Volume 9, issue 1-6

Authors: Srivastava, Sudhir | Grizzle, William E.

Article Type: Editorial

DOI: 10.3233/CBM-2011-0158

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 1-4, 2011

Authors: Grizzle, William E. | Srivastava, Sudhir | Manne, Upender

Article Type: Research Article

Abstract: With the increasing use of individualized medical care (personalized medicine) in treating and managing patients with cancer, the utilization of biomarkers in selecting and tailoring such medical approaches also is increasing and becoming more important. Specifically, many therapies are effective against only a subgroup of a specific type of tumors and exposing patients with different non-responsive subgroups of the same tumor to ineffective therapies, not only exposes these patients needlessly to acute and chronic side effects of the therapy, but also adds to the costs of medical care. For example, the Oncotype Dx test for estrogen receptor positive tumors that …are node negative has been used to identify low risk tumors for which surgery alone is an adequate therapy. Biomarkers may be used to aid in multiple aspects of medical care related to cancer, including early detection, diagnosis, risk assessment, as well as in predicting the aggressiveness of cancers (i.e., prognosis) and predicting the therapeutic efficacy of treatments (i.e., prediction). Biomarkers may be also used as surrogate endpoints to aid in evaluating therapies and preventive approaches. Types of biomarkers vary greatly and include histopathologic appearance, stage of the lesion, quantitative morphologic features, size of the lesion, metastatic pattern and extent of metastasis, as well as imaging and molecular features. The types of measurements of biomarkers also vary; for example, molecular features can be measured at the DNA, mRNA or protein levels as well as at regulatory levels (e.g., microRNA). The usefulness of each biomarker is limited by its sensitivity and specificity in fulfilling its role (e.g., in early detection) and the requirements of sensitivity and specificity to accomplish specific tasks are affected by multiple variables. For example, both very high specificity and sensitivity of a test are required to screen a population with a low prevalence of a specific tumor. The goal of this manuscript is to introduce the reader to how biomarkers may be used and the limitations on the uses of biomarkers in translational research. Show more

Keywords: Sensitivity, specificity, early detection, prognosis, risk assessment, surrogate endpoints, diagnosis, receiver operating characteristic, prediction, biomarkers, prevalence, medical costs, side effects, histopathology, molecular features, imaging, prevention, treatment, personalized medicine, individualized medical care

DOI: 10.3233/CBM-2011-0159

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 7-20, 2011

Authors: Grizzle, William E. | Srivastava, Sudhir | Manne, Upender

Article Type: Research Article

Abstract: Invasive tumors (cancers or malignant lesions) typically develop in the setting in which there is the presence of putative non-invasive lesions and the development of these non-invasive lesions frequently precedes the development of cancers. For some organs, such as the oral cavity, cervix and skin, the respective putative pre-invasive lesions can be observed over time and documented to progress to invasive lesions. However, for less readily observable lesions, such as those of the prostate, the progression of the pre-invasive lesions, e.g., prostatic intraepithelial neoplasia (PIN) and prostatic proliferative inflammatory atrophy (PIA) to prostatic cancer are more difficult to document. Thus, …for most organ systems, specific pre-invasive neoplastic lesions have been proposed based upon the apparent observations of one or more of the following: 1) microinvasive disease developing from a pre-invasive neoplastic lesion, 2) the general association of the pre-invasive lesion with invasive lesions, 3) the subsequent development of invasive lesions following diagnosis of the pre-invasive lesion, 4) correlations of the molecular features of the putative pre-invasive lesion with the matching invasive lesions, and 5) reductions in the rate of cancer following removal of the pre-invasive lesion. When there are mixtures of pre-invasive lesions with actual cancers in the same case, some of the above specific associations are more difficult to make. Several terms have been used to describe pre-invasive lesions, many of which are now less useful as our knowledge of these lesions increases. It is now commonly accepted that these lesions are a features of the spectrum of neoplastic development and most are accepted as ``neoplastic lesions'' with associated molecular features, even though they may be reversible even if they have mutations in suppressor genes (e.g., p53) or are associated with viral etiologies (e.g., cervical intraepithelial neoplasia). The overall term, "pre-invasive neoplasia", seems to best describe these putative pre-invasive lesions. Thus, terms such as incipient neoplasia should be abandoned. The term "intra-epithelial neoplasia" with an associated grade, which has been developed for pre-invasive neoplastic lesions of the cervix, i.e. cervical intraepithelial neoplasia (CIN), seems to be a terminology that adds consistency across epithelial organs. Thus, adoption of these terms for the additional organ sites of pancreas (PanIN) and prostate (PIN) seems accepted. Less descriptive terms such as the degrees of dysplasia of the oral cavity and bronchopulmonary system and actinic keratosis and Bowen's disease of the skin might be better designated as oral intraepithelial neoplasia (OIN), pulmonary intraepithelial neoplasia (PulIN) and dermal intraepithelial neoplasia (DIN). The etiology of pre-invasive neoplasia is the etiology of the matching cancers. Some obvious initiating factors include exposure to the whole range of ionizing and non-ionizing radiation, tobacco abuse and a broad range of other carcinogens (e.g., benzene). A frequent initiation factor is the setting of long standing continuing damage, inflammation and repair (LOCDIR) which leads to early molecular features associated with neoplasia after about one year. An excellent example of this is ulcerative colitis (UC) in which dysregulation of microsatellite repair enzymes have been documented one year following diagnosis of UC. While the nomenclature, description, diagnosis and etiology of pre-invasive neoplasia has advanced, approaches to therapy of such lesions have not progressed adequately even though it has been identified that, for example, removal of polyps periodically from the colorectum, DCIS from the breast, and high grade CIN from the cervix, results in a reduction in the development of cancers of the colorectum, breast, and cervix, respectively. With the development of more molecularly targeted therapy with fewer side effects, preventive therapies may be more successfully targeted to pre-invasive neoplastic lesions. Show more

Keywords: Intraepithelial neoplasia, pre-invasive neoplasia, prostatic intraepithelial neoplasia, pancreatic intraepithelial neoplasia, cervical intraepithelial neoplasia, adenomatous polyps, ductal carcinoma in situ, lobular carcinoma in situ, inflammation, radiation, viral infections, carcinogens, dysplasia, actinic keratosis, repair, angiogenesis, LOCDIR

DOI: 10.3233/CBM-2011-0172

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 21-39, 2011

Authors: Srivastava, Sudhir | Grizzle, William E.

Article Type: Research Article

Abstract: It has become increasingly evident that the study of DNA is inadequate to explain many, if not most, aspects of the development and progression of neoplastic lesions from pre-invasive lesions to metastasis. Thus, the term "genetic" can no longer refer to just the study of the genome. Much of the action in genetic research now shifts to the methods by which the pre-mRNA from one gene is processed to yield multiple different proteins, different quantities of the same protein as well as other forms of regulating RNA. Thus, the age of post-transcriptional processing and epigenetic control of the transfer of …information from the genome has arrived. The mechanisms of post-transcriptional processing and epigenetic control that must be characterized in greater detail including alternate splicing, regulation of mRNA degradation, RNA regulatory factors including those factors which extensively edit mRNAs, control of translation, and control of protein stability and degradation. This chapter reviews many of the processes that control information from the genome to proteins and how these factors lead from less than 40,000 genes to more than an order of magnitude increase more proteins which actually control the phenotypes of cells – normal or neoplastic. It is usually the products of genes (e.g., mRNA, microRNA and proteins) that are the molecular markers that will control translational research and ultimately, individualized (personal) medical approaches to disease. This chapter emphasizes how the process of neoplasia “hijacks” the normal processes of cellular operations, especially those processes that are important in the normal development of the organisms – including proliferation, cellular death, angiogenesis, cellular mobility and invasion, and immunoregulation to ensure neoplastic development, survival and progression. This chapter reviews the wide range of processes controlling the information that flows from the genome to proteins and emphasizes how molecular steps in pure processes can be used as biomarkers to study prevention, treatment and/or management of diseases. Show more

Keywords: Intraepithelial neoplasia, dysplasia, methylation, microsatellite instability, mutations, insertions, deletions, oncogenes, suppressor genes, aneuploidy, translocations, caretakers, gatekeepers, landscapers, mismatch repair genes, LOCDIR, epigenetics, immunoregulation, tumor associated fibroblasts, exosomes, angiogenesis, clonal selection, viral insertions, biomarkers, validation

DOI: 10.3233/CBM-2011-0204

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 41-64, 2011

Authors: Natarajan, Thanemozhi G. | Ganesan, Natarajan | FitzGerald, Kevin T.

Article Type: Research Article

Abstract: In an effort to improve our understanding and treatment of cancer, a new model of tumorigenesis is being developed – the cancer stem cell model. Building upon traditional concepts of cancer and stem cells, this model is intended to shed new light on the continuing struggle with treatment challenges such as tumor drug-resistance and recurrence. This review describes the cancer stem cell model with an emphasis on delineating markers that represent a "stemness" phenotype within certain tumor cells. The objective of this delineation is to develop targeted therapies for the selective elimination of cancer stem cells with minimal toxicity to …normal stem cells and tissues. However, this specific targeting of cancer stem cells has proved to be a significant challenge due to the similarity of markers expressed by both normal and cancer stem cells. Still, research in the area of cancer biomarkers is steadily progressing. Show more

Keywords: Cancer, stem cells, markers, stemness, asymmetric division, stem cell niche, immortality, canonical pathways, signaling pathways, surface antigens, transcription factors, detoxifying proteins, communication, clinical implications

DOI: 10.3233/CBM-2011-0173

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 65-99, 2011

Authors: Carmona, F. Javier | Esteller, Manel

Article Type: Research Article

Abstract: Life expectancy rises steeply when a tumor is diagnosed at an early stage. Therefore, diagnosing cancer before it turns into an aggressive, barely curable disease is one of the main goals of oncological research in the 21st century. This is of vital importance for certain types of cancer for which survival rates drastically drop as primary tumors are detected by currently available screening procedures. Aberrant DNA methylation is a common hallmark of human cancer. This epigenetic mark is altered in instructive ways in the distinct stages of multistep tumorigenesis from the early onset of malignant transformation. Therefore, the possibility of …detecting precise methylation signatures associated with particular cancers and the development of methodologies increasingly sensitive at detecting them, makes DNA methylation biomarkers attractive predictors for the development of effective diagnostic tests for the early detection of human neoplasia. Show more

Keywords: DNA methylation, cancer, biomarker, early detection, screening

DOI: 10.3233/CBM-2011-0184

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 101-111, 2011

Authors: Sen, Subrata | Hopwood, Vicki

Article Type: Research Article

Abstract: There is strong evidence that multistep tumorigenesis begins with the acquisition of somatic mutations which promote genomic instability. Genomic instability is an important malignant trait because genomic instability can generate the genetic diversity that is necessary for the transforming cell to acquire increasingly variable and aggressive tumor phenotypes. Genomic instability often manifests in the form of chromosomal instability (CIN) leading to the induction of aneuploidy, a phenomenon identified by high resolution molecular cytogenetic techniques. Fluorescent in situ hybridization (FISH) and Array Comparative Genomic Hybridization (aCGH) are two high resolution molecular cytogenetic techniques that allow detection of chromosomal aneuploidy and structural …rearrangements occurring in pre-malignant and malignant lesions during tumor progression and invasion. These high resolution molecular cytogenetic techniques are used for genetic screening of single cells in pre-malignant and precursor malignant lesions as well as in exfoliated cells from body fluids and excreta. Consequently, molecular cytogenetic testing offers the promise of an extremely powerful method of risk assessment and early detection of cancer. Show more

Keywords: Chromosomal instability (CIN), aneuploidy, genetic mutation, microenvironment, chromosomal rearrangements, gene amplification, gene fusion, chromosome deletion, spindle assembly checkpoint, Fluorescence in situ hybridization (FISH), Array Comparative Genomic Hybridization (aCGH)

DOI: 10.3233/CBM-2011-0171

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 113-132, 2011

Authors: Wang, Wendy | Srivastava, Sudhir

Article Type: Research Article

Abstract: Molecular biomarkers are widely recognized as having tremendous utility in cancer early detection, prediction, and prevention. Huge efforts have been put into searching of various molecular biomarkers for these purposes, yet there are few molecular biomarkers that have been approved by the Food and Drug Administration for clinical use. Discovery of novel molecular biomarkers is still urgently needed to create biological insights into early events of carcinogenesis and to predict the aggressiveness of early cancer. Noncoding RNAs (ncRNAs) are relatively unexplored molecules identified only one decade ago. With research on the basic biology and mechanisms of ncRNAs, they have rapidly …been linked to etiology of diseases, particularly cancer. In this chapter, we will summarize ncRNAs, particularly microRNAs (miRNAs), a type of ncRNAs, as a new frontier for the discovery of cancer biomarkers in preneoplastic lesions and their usefulness as markers for the risk assessment, early detection, and diagnosis of cancer. Show more

Keywords: Noncoding RNAs (ncRNAs), microRNAs (miRNAs), cancer, biomarkers, early detection, diagnosis, biomarker validation, cancer risk assessment, oncogene, tumor suppressor

DOI: 10.3233/CBM-2011-0179

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 133-140, 2011

Authors: Liu, Alvin Y. | Pascal, Laura E. | Vêncio, Ricardo Z. | Vêncio, Eneida F.

Article Type: Research Article

Abstract: In prostate tumors, both the epithelial and stromal mesenchyme compartments show gene expression changes from their respective normal counterpart. In fact, there are more such changes in the stroma than the epithelium. These include down-regulated expression of genes involved in smooth muscle cell differentiation and those differentially expressed between prostate and bladder, i.e., organ-restricted. In development, the stromal cell type mediates tissue formation from differentiation of stem or progenitor cells. Diseases like cancer may arise as a result of defective stromal signaling. Stromal signaling can be demonstrated by co-culture of stromal cells and embryonal carcinoma NCCIT cells used as a …stem cell substitute. In co-culture, stromal cells induce NCCIT cells through diffusible molecules to lose stem cell gene expression, gain expression of prostate genes, alter cytomorphology, and lower proliferation. This NCCIT response is varied as co-cultured bladder stromal cells induce a different gene expression. At the same time, NCCIT factors also affect gene expression of co-cultured stromal cells. NCCIT induces normal prostate tissue (NP) stromal cells to become more like cancer-associated (CP) stromal cells in both mRNA and microRNA expression. In contrast, NCCIT shows minimal effect on CP stromal cells. CP stromal cells may represent a less differentiated state in the prostate stromal cell lineage. Show more

Keywords: Prostate cancer, cell type transcriptomes, CD26+ cancer cells, CD90+ cancer-associated stromal cells, Gleason patterns, stromal induction of stem cells, NCCIT embryonal carcinoma cells, in vitro co-culture, cell-cell interaction, intercellular signaling molecules, mRNA and miRNA expression changes

DOI: 10.3233/CBM-2011-0174

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 141-155, 2011

Authors: Czerniak, Bogdan

Article Type: Research Article

Abstract: Bladder cancer originates in the epithelial lining of the bladder's mucosa and develops in association with several habitual, industrial, and environmental risk factors via papillary and non-papillary pathways. In this chapter we review novel concepts concerning the molecular mechanisms of early field change in bladder neoplasia stemming from whole-organ genomic mapping studies. These mechanisms are discussed in the context of molecular pathogenesis of bladder cancer and in relation to treatment and biomarker-based detection strategies.

Keywords: Bladder cancer, dual-track pathway, genomic map, biomarkers, risk factors, forerunner genes, precursor lesions, field effect, molecular profiling, diagnosis and treatment of bladder cancer

DOI: 10.3233/CBM-2011-0175

Citation: Cancer Biomarkers, vol. 9, no. 1-6, pp. 159-176, 2011