Molecular Oncology: Principles and Recent Advances

Tight control of the cell cycle in eukaryotic cells exists to control proliferation, differentiation or apoptosis. These processes model and shape tissue and organ relationships in multicellular organisms. Two biochemical processes, protein phosphorylation/dephosphorylation and ubiquitin-mediated degradation drive cell cycle control. A multitude of pathways control cyclin-dependent kinase activities as the major event for cell cycle progression. Differentiation and apoptosis have cell cycle withdraw in common, while cancer and degenerative processes both show altered control of the cell cycle.

There is a close and direct relationship between the magnitude of the exposure of compounds in the environment that disrupts its natural equilibrium and the development of disease. Many of these substances act as mutagens or promoters or synergistically behave as carcinogens, and thus contribute to the growing incidence of cancer worldwide. However, the underlying mechanisms involved in the induction of genomic instability, genotoxicity, mutations and consequent increased cell proliferation are still a matter of intense research. In particular, tobacco smoke, exposure to radiation, pesticides, dioxins, organic compounds, metals and metalloids, and outdoor air pollution, will be reviewed with respect to epigenetic events, genetic polymorphism susceptibility, gene expression and signal transduction modification, and oxidative stress cellular events related to carcinogenesis.

Obesity is the largest pandemic, the human being has undergone. Obesity has been linked to several health-related problems, but recent epidemiological studies have uncovered a link between excess body weight and certain types of cancers. We have begun to realize the complexity of the biological mechanisms that link obesity and being overweight to many forms of cancer. In this chapter, I briefly review these epidemiological findings and the three molecular pathways currently proposed to link body weight gain and cancer risk. Despite the fact that these molecular pathways, vary and depend on both sex and the type of cancer, I briefly discuss the possible roles of three hormonal systems, the adipose derived hormones, the Insulin-Like Growth Factor (IGF) axis and sex steroids, in linking obesity and cancer risk.

Estrogens are compounds that have a wide range of activities in the human body. These hormones regulate processes, such as the ovarian cycle, sexual development, preparation for implantation of fertilized embryos, and others. The most abundant estrogen in humans is estradiol. It exerts its effects through an estrogen receptor that functions as a transcriptional factor. The mechanism of action of estrogens involves the recruitment of co-regulator proteins that allow, or not, classical transcriptional activity and the transcriptional activation or repression of target genes. Non-genomic actions of estrogens have been reported, and these effects are mediated by a G-coupled protein receptor. Estrogens not only participate in physiological processes, they are also involved in pathology, such as cancer. Breast cancer is one of the main cancers that is affected by estrogens, as there is a higher expression of estrogen receptor α in breast cancer than in normal breast tissue. In this way, estrogens also participate in the development of other cancers including colon, ovarian and cervical cancer. Pharmacological strategies for estrogen related cancer treatments have been developed. Selective Estrogen Receptor Modulators (SERMs) and Aromatase Inhibitors (AIs) have been developed to antagonize the effects of estrogens, or estrogen synthesis, respectively. The use of tamoxifen and other compounds are effective in the treatment of some cancers, including breast cancer. Furthermore, change in lifestyle choices to help reduce xenoestrogen exposure is also a step that a woman can take to control total estrogen exposure.

Primary liver cancer is the sixth most common cancer in the world and the third cause of death by cancer due to its bad prognosis. Most primary liver cancers are Hepatocellular Carcinomas (HCC). The major risk factors for HCC are chronic liver diseases (especially cirrhosis) including hepatitis B and C, alcoholic liver disease, non-alcoholic steatohepatitis, estrogens, and well documented environmental preventable risk factors, among others. Rho, hepatocyte growth factor, and metalloproteinases are associated with metastasis and death from HCC.

Cervical Cancer (CC) is a major cause of cancer mortality and is caused by persistent infection with High-Risk Human Papillomavirus (HR-HPVs). Infection occurs primarily at the transformation zone (the most estrogen and retinoid sensitive region of the cervix). Development of CC affects a small percentage of HR-HPVinfected women and often takes decades after infection suggesting that HR-HPV is a necessary but not sufficient cause of CC. Thus, other cofactors are necessary for progression from cervical HR-HPV infection to cancer such as long-term use of hormonal contraceptives, multiparity, smoking and retinoid deficiency which alter epithelial differentiation, cellular growth and apoptosis of malignant cells. Thereby, the early detection of HR-HPV and management of precancerous lesions together with a profound understanding of other risk factors could be a strategy to avoid this disease. In this review, we focus on the synergic effect of estrogens, retinoid deficiency and HR-HPVs in the development of CC. These risk factors may act in concert to induce neoplastic transformation in squamous epithelium of the cervix, setting the stage for secondary genetic or epigenetic events leading to carcinogenesis.

Randomly occurring mutations of oncogenes and genetic or epigenetic alterations of tumor suppressor genes control many important cellular processes, such as proliferation and apoptosis, involved in human cancer. These genes, as well as those encoding enzymes participating in DNA repair, telomere elongation, inflammation and angiogenesis are the major players during multi-step carcinogenesis. A very important characteristic of oncogenes is that they are active genes that cooperate to induce a transformed phenotype. There are many experimental examples supporting this cooperation, including oncogene transfection studies in cell lines and transgenic mice containing activated oncogenes. These systems and those indicating loss of function in tumor suppressor genes have been models of gene collaboration and multi-step transformation. Alterations disrupting the balance between growth-promoting and growth-inhibiting pathways can lead to cancer, but these alterations can explain only part of the human cancer pathogenesis. The complex mechanisms for regulating apoptosis and the eukaryotic cell cycle are prime targets for oncogenic and tumor suppressor mutations. Only the mutations striking the cancer stem cell population can be transmitted to descendant cells due to their unlimited proliferative potential. It seems that the widespread destabilization of cancer stem cell genomes occurs quite early in multi-step tumor progression. All these findings help molecular oncologists to prevent, diagnose and treat human cancer in more specific ways.

In most cancers, a number of epigenetic alterations occur during all stages of carcinogenesis. These include global DNA hypomethylation, hypermethylation of key tumor suppressor genes, and histone modifications. Unlike genetic alterations, which are almost impossible to reverse, epigenetic aberrations are potentially reversible, allowing the malignant cell population to revert to a more normal state. With the advent of numerous drugs that target specific enzymes involved in the epigenetic regulation of gene expression, the utilization of epigenetic targets is emerging as an effective and valuable approach to chemotherapy. This revision is an overview of general epigenetic aspects involved in cancer and the potential utilization of drugs with effects in epigenetic targets that could be useful in cancer therapy.

Signal transduction has proven to occur not through linear pathways linking individual receptors to specific cellular responses, but rather, occurs through a set of interconnected pathways which form complex signaling networks. Some key pathways, such as Ras-Raf-MEK-ERK, PI3K-Akt-NF-κB, JAK-STAT, and Src are often initiated by receptor tyrosine kinases. They function as entry points for many extracellular cues, and play a critical role in recruiting the intracellular signaling cascades that orchestrate a wide range of biological processes regulating essentially all aspects of normal and malignant cell behavior. It is clear that enhanced or deregulated signaling can generate signals leading to tumor growth and metastasis. Herein, defects in the apoptotic signaling pathways, which have been recognized as a hallmark of cancer, are described with particular focus on the key players of intrinsic pathway of apoptosis.

Metastasis is a complex sequence of processes that take place when a tumor cell exits the primary tumor, and establishes a secondary tumor by traveling to a distant site via the circulatory system. The complex process of metastasis depends on various components for successful dissemination and tumor cell growth at a secondary site. Metastatic processes include: (1) neoplastic progression, (2) angiogenesis, (3) migration and invasion, (4) intravasation, (5) circulation and embolism, (6) extravasation, and (7) metastatic tumor establishment in the target tissue. In this chapter we will discuss the steps involved in the complex process of tumor metastasis and the molecular mechanisms that underly each one of these steps.

It is known that the immune system through innate and adaptive immune responses plays an important role to detect and eliminate primary chemically induced or spontaneous tumors. However, according to clinical data and experimental studies using de novo immune-competent mouse models of cancer development, the immune system can also participate as cancer-promoter. In this regard, deficient anti-tumor cell-mediated immunity, in combination with enhanced pro-tumor humoral and/or innate immunity (inflammation), are significant factors influencing malignant outcome. This review describes current knowledge of the interaction between tumors and the immune system, cellular and molecular events that favor tumor immune tolerance and current approaches to control tumor growth trough immunotherapy as well as novel strategies to block immunosuppressive elements.

Nowadays cancer kills thousands of humans around the world, so its research presents an important challenge to decrease cancer mortality. Strategies for cancer research have made great advancement in the last century, providing major insight into the complexity of tumor development. Numerous experimental protocols for many years have been performed to mimic features of cancer cells in humans; for example, to generate tumors in living organisms and study cancer in cultured cells. This chapter describes several of theses biological models: 1) chemical carcinogenesis protocols 2) genetically modified animals (transgenic and knockout mice), 3) cancer cell lines culture, 4) gene manipulation in cultured cells such as DNA transfection and RNA interference for gene knockdown and 5) the concept of cancer stem cells. The significance of in vivo and in vitro models for cancer research lies in the possibility of providing improved understanding of cancer biology and cancer treatment.

Detection of DNA and RNA alterations and proteins associated with cancer are used as indicators or biomarkers for specific tumor traits that help in cancer diagnosis and patient management. Molecular diagnosis in cancer is a new discipline that incorporates genomic and proteomic information related to malignant, premalignant and normal tissues from which clinically useful cancer biomarkers are expected to be identified. The goal is to find and clinically validate biomarkers associated with cancer risk, early detection, phenotypic tumor aggressivity, tumor staging, or biomarkers associated to prognosis such as response to treatment, disease recurrence and survival. Challenges for achieving this goal arise from a need of significant economic investment, as well as a multidisciplinary approach and the inherent molecular complexity of cancer itself.

The successful use of chemotherapy in the treatment of several diseases has been one of the great drug development stories of the last century. Motivated by this, we present here an overview of the various steps required to develop a new drug treatment. An introductory view of the field of medicinal chemistry is provided as an example to a broad discipline that has successfully designed procedures that are routinely used for drug development. A detailed view of the subfield of bioinorganic medicinal chemistry is then presented which describes the research and development involved in the design of new metal-based drugs. A specific example of the development of the CASIOPEINAS® family compounds, a set of copper based molecules is used to illustrate the wide range of strict scientific procedures involved from initial design to the final registration of the drug.

The effects of many anticancer drugs are unfortunately masked by drug resistance developed by several tumors. This represents a strong and major challenge in cancer research. Drug resistance is due to several factors, including membrane transporters taking out drugs from the cell, molecular mechanisms repairing or inhibiting the damage caused by the drugs, mutations in anticancer drug targets, or even anatomic structures affecting either drug penetration or elimination. Here we will review the molecular aspects of therapy resistance mechanisms. Research on the inhibition of proteins involved in drug resistance or design of new anticancer drugs overcoming such mechanisms with no doubt will result in a major advancement in cancer treatment.

Gene therapy allows the specific control of disease-associated genes. It has been used to target specific genes on different types of cancer. A singular approach to regulate gene expression includes the administration of small synthetic Therapeutic Nucleic Acids (TNAs) which include Antisense Oligonucleotides (AS-ODNs). ASODNs utilize DNA sequence information from a disease gene to synthesize a molecule complementary to an accessible target mRNA. Although, many AS-ODNs have shown promising results targeting specific genes in different cancer types at a preclinical stage, only few of them have entered clinical trials. In this review, we will focus on the most successful AS-ODNs administered in clinical trials. The use of AS-ODNs on the clinical set up often produced unexpected results, suggesting that design and pre-clinical modifications are required to improve responsiveness to treatment. It is important to note that even though these molecules show advantage over conventional drugs for treating disease, the use of AS-ODNs as standard therapy for cancer is still far.

Basic oncology concepts as well as recent discoveries in cancer research have been described throughout this book. This final chapter aims to present some suggested directions in future cancer research based on both the information provided in this book and on the current high throughput technology available today. Several ideas arise, from prevention and epidemiological studies to gene expression and proteomic in a personalized-based manner. Definitely, interaction of the diverse cancer experts in the world should lead to a better understanding of this disease. Multidisciplinary cancer research should also lead to discovery of more accurate methods to diagnose the disease at early stages and provide more efficient anti-cancer therapies, to the benefit of cancer patients.