Mitoproteases display an essential role in the preservation of mitochondrial homeostasis under regular and stress conditions. These enzymes perform tightly regulated proteolytic reactions by which they participate in mitochondrial protein traffcking, processing and activation of proteins, protein quality control, regulation of mitochondrial biogenesis, control of mitochondrial dynamics, mitophagy, and apoptosis. In this chapter, we have revised the physiological functions of the intrinsic mitochondrial proteases, analyzing their roles in the different compartments of this organelle and their connection to human pathology, primarily cancer, neurodegenerative disorders, and multisystemic diseases.
Genome stability is maintained by a number of elegant mechanisms, which sense and repair damaged DNA. Germline defects that compromise genomic integrity result in cancer predisposition, exemplifed by rare syndromes caused by mutations in certain DNA repair genes. These individuals often exhibit other symptoms including progeria and neurodegeneration. Paradoxically, some of these deleterious genetic alterations provide novel therapeutic opportunities to target cancer cells; an excellent example of such an approach being the recent development of poly (ADP-ribose) polymerase inhibitors as the frst ‘synthetic lethal’ medicine for patients with BRCA-mutant cancers. The therapeutic exploitation of synthetic lethal interactions has enabled a novel approach to personalised medicine based on continued molecular profling of patient and tumour material. This profling may also aid clinicians in the identifcation of specifc drug resistance mechanisms following relapse, and enable appropriate modifcation of the therapeutic regimen. This chapter focuses on therapeutic strategies designed to target aspects of the DNA damage response, and examines emerging themes demonstrating mechanistic overlap between DNA repair and neurodegeneration.
Today’s cancer patients are better informed than ever before. Manypatients come to their doctor equipped with a stack of literature and a good understanding of their diagnosis and treatment. But a crucial component is missing. Most patients have no idea that the quality of their treatment is a key factor that can influence their survival. Making matters worse is the fact that even if patients were aware of this issue, they don’t have the tools to evaluate whether their team is providing top-notch care. When a patient receives recommendations from her doctor, it is very difficult to know if those recommendations are good ones. In many instances, she may never know if her doctor has made a critical mistake. Delivering cancer treatment to patients is very complex. Treating cancer is not like following a simple recipe, where mixing the same ingredients in any kitchen gives the same results. Cancer care for a single patient requires decisions from numerous professionals to dispense treatments that are potentially life-saving, but also potentially dangerous and life-threatening. The chances of cure and survival for any given patient depend on the expertise of the cancer team and whether procedures are in place to ensure that cancer care is delivered properly.
Given the extensive history of cancer, the history of patient-derived xenograft (PDX) models is also diffcult to fully recapitulate. In particular, this task is complicated by the irregularity with which PDX models were designated. The current use of “PDX cancer models” is a relatively recent addition to the lexicon. However, the general concept of PDX models—i.e., the transplantation of human cancers into animal models—can be found throughout the chronicles of cancer research. However, it wasn’t until the discovery of host immunity and its crucial role in graft survival that the idea of serial transplantation could be realized. Therefore, in order to better reﬂect the nature of its history, the term “human tumor models” will be used in place of “PDX models,” except when appropriate. Finally, it is important to also mention the existence of the other labels that have been used, including, but not limited to, “human tumor xenografts,” “xenopatients,” heterotransplant tumor models,” “heterotransplanted human tumors,” and “transplantable tumor models.”
More than a century ago, the Nobel Prize for Physiology or Medicine (1908) was awarded jointly to Ilya Mechnikov and Paul Ehrlich “in recognition of their work on immunity” and it was around this time that Ehrlich expounded his hypothesis that the immune system may play a role in the control of tumours . However his suggestion was actually preceded by work carried out by a young New York bone surgeon, William Coley (1862–1936) who had read about a patient who underwent dramatic regression of a neck tumour after developing erysipelas, a skin infection caused by streptococcus pyogenes. Coley subsequently observed that his own patients who developed post-operative infection after surgery seemed to gain some improvement in outcome with respect to their underlying sarcomatous tumours. He believed that these infections may have stimulated the immune system in a way that rendered it more capable of recognising and attacking the cancer. He developed Coley’s toxin comprising killed bacteria, provided by Robert Koch, and he injected this into his patients, reporting a complete regression rate in inoperable sarcomas of approximately 10% . Although the use of Coley’s toxin declined rapidly in the 1950s with the ﬂourishing of cytotoxic drugs and radiotherapy, there are still clinics today that use a variation of this agent comprising Streptococcus pyogenes and Serratia marcescens.
In recent years the treatment of cancer patients has profoundly changed, thanks to the study and the comprehension of the biological processes underlying tumor development and progression. Almost 20 year ago was first used the term “oncogene addiction ” to describe the phenomenon where the activation of a specific oncogene is required for cancer cell survival and proliferation . It was then supposed that a pharmacological agent, able to specifically target the hyperactivated oncogene , was efficient to selectively kill cancer cells sparing normal cells from toxicity. This is no longer a dream, but it has become part of clinical real life for oncologists and their patients. Since then clinicians have changed the way to treat and select patients for a specific treatment, moving from one-size-fits-all strategy to the so-called precision medicine that is based on a correct patient’s selection. Patient’s selection is based on a series of molecular biology procedures able to define a specific molecular profile for the tumors. Therefore, until now, the path of cancer patients’ survival is tissue dependent (Fig. 1.1). The identification of a specific gene status in a precise tumor type (e.g., c-KIT for gastrointestinal stromal tumors or EGFR in non-small cell lung cancer) enables the selection of the patient for a targeted therapy . If considered the abovementioned examples, for those patients in which the molecular analysis does not provide any information (wild-type patients), the strategy is the standard treatment indicated for their disease. Moreover, we are now witnessing another revolution brought from immunotherapy, but that’s another story beyond the scope of this volume .
Pancreatic cancer (PC) is one of the leading causes of cancer deaths worldwide. It is the fourth leading cause of cancer-related death in both men and women in the United States and has <10% 5-year overall survival rate for all stages . Worldwide, PC is the eighth leading cause of cancer death in men (about 138,100 deaths annually) and the ninth in women (about 127,900 deaths annually). In general it affects more individuals residing in the Western and industrialized parts of the world with the highest incidence reported in New Zealand, Black American and Hawaiians and the lowest incidence reported among people living in Nigeria and India . Based on data obtained from the surveillance epidemiology and end results (SEER) database, the incidence and death rate of PC is 12.4 and 10.9 per 100,000 men and women per year, respectively. In the United States, an estimated 53,070 people will be diagnosed with PC in the year 2016, and 41,780 people will die secondary to it . PC occurs less commonly before age 45, but its incidence rises sharply thereafter with more than half of the patients over 70 years at diagnosis. As the average lifespan is expected to increase in the future, it is likely that PC would become more prevalent. Over 85% of exocrine PCs are adenocarcinomas with other variants making up the rest . Majority of PCs are idiopathic in nature with exception of few cases where an actual risk factor could be identifed. Some of the nonfamilial risk factors that have been identifed which may contribute to the development of PC include smoking, alcohol, diabetes, impaired glucose metabolism, insulin resistance, obesity, infections, coffee and non-blood group ‘O’. Age is considered one of the most common risk factors with an obvious dramatic increase in incidence of PC as one gets older. Racial factor may play a role in development and outcome of PC.
Obesity is now a well-established promoter of cancer progression and decreased overall patient survival. Ever since the association between obesity and cancer was appreciated, adipose tissue, adipocytes, and secreted fat-derived factors have been a focus of the mechanism underlying this link. Adipose-secreted factors cytokines are referred to as adipocytokines and represent the group of molecules thought to link adipose or fat cells to initiation and promotion of various cancers. There are over 20 identified adipokines, of which, a subset has been implicated in cancer. In this chapter, we will provide a concise review of the current literature on the subset of adipose-derived factors linked to cancer.
Oral cancer is a major health burden particularly in the developing world where most of the cases are diagnosed . More than 300,000 new patients are estimated to be diagnosed with oral and oropharyngeal cancer in 2012, and 50% of these cases will die annually . The WHO International Statistical Classifcation of Diseases (ICD-10) defned oral and oropharyngeal cancer as the malignancy emerging from the anatomic sites that correspond to the rubrics C00–C10 of the ICD-10 . Specifcally, the involved oral anatomic subsites include the lips, buccal mucosa, alveolar ridge and gingiva, retromolar trigone, anterior two-thirds of the tongue (anterior to the circumvallate papillae), ﬂoor of the mouth and hard palate. The oropharynx (middle part of the pharynx) consists of the soft palate, base (or posterior one-third) of the tongue, palatine tonsils, palatoglossal folds, valleculae and posterior pharyngeal wall. Traditionally oral cancer was sometimes used to designate head and neck cancer that genuinely covers wider anatomical region with more heterogeneous nature. Though, for the purpose of this chapter, lip/mouth and oropharyngeal cancers have been combined and termed as oral and oropharyngeal cancer (OPC). Also, the cases originated from either nasopharynx or other pharynxes were excluded to distinguish it from the head and neck cancer. Squamous cell carcinoma is the most common type of malignancy that is diagnosed in the oral and oropharyngeal region with more than 95%.
While connoting both the social as well as biological consequences of an entity that has plagued mankind for millennia, this sentiment recognizes the central role of the immune system in wound healing, or, in this context, tumor elimination. The critical role that the immune system plays in tumor regression, and therapeutic strategies harnessing the host immune response against tumor, have been recognized since the advent of Coley’s toxin over a century ago—based on observations that patients with severe postoperative skin infections after their sarcoma surgery would spontaneously achieve cancer remission. Bacillus Calmette–Guérin (BCG) vaccine has shown durable effcacy in localized bladder cancer with reported responses in etastatic cancers as well. Decades of innovation in medical science would be required to further refne cancer immunotherapy for clinical use.