Tissue Stiffness as a Risk of Cancer Development and Impact on Clinical Outcome in Solid Tumors: A Systematic Review (Cancer Etiology, Diagnosis and Treatments)

This chapter is a monography concerning the possible role of tissue stiffness in the human carcinogenesis as well as its possible impact in the diagnosis, prognosis, and treatment of the malignancies. Cancer is a very serious health problem in mankind, with an increasing prevalence and incidence worldwide. Although in the last years, several diagnostic and therapeutic approaches were suggested and made available for managing human malignancies, the outcome of patients and their quality of life are still poor for most of these different forms of neoplasms (Torre LA, Siegel RL, Ward EM, Jemal A., Cancer Epidemiol Biomarkers Prev. 2016;25(1):16-27. doi: 10.1158/1055-9965.EPI-15-0578). Several reasons may explain this dismal prognosis: the aggressive biological behavior of some histological subtypes, the acute-, intermediate- or late- side effects of systemic chemotherapy and radiotherapy, including toxicity of organs, diarrhea, skin irritation, nausea, mucositis, alopecia, vomiting, intestinal discomfort, asthenia, the arising of immunosuppression with neutropenia, the increased risk of infections as well as the occurrence of secondary cancers, at variable time intervals, either within a few weeks or months/years after the end of anticancerous treatments. From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review). Int J Oncol.] 2019;54(2):407-419. doi: 10.3892/ijo.2018.4661). 1) Novel strategies and methodological approaches are strongly required to determine an effective improvement in the management of these diseases. It is conceivable to suppose that not only the genetic alterations, but also further important factors may be involved in determining the prognosis of patients, suffering from malignancies. 2) Extracellular matrix (ECM) represents a crucial and key component of tissue structure contributing to the initiation, growth, and progression of human carcinoma. This last consists of a three-dimensional and highly dynamic macromolecular network, supporting the structure of all mammalian cells and modulating their function. ECM is characterized by well-defined physical, biochemical and biomechanical properties and plays multiple functions, such as: a) the maintenance of cellular, tissue and organ homeostasis, b) the regulation of both the amounts and the activities of growth factors and receptors c) the preservation of an adequate hydration status and pH level in the tissue microenvironment. It undergoes a continuous but tightly regulated remodeling and several mechanisms participate in the control of its adequate composition and structural organization. Therefore, ECM regulates a wide series of distinct cell activities, such as differentiation, apoptosis, proliferation and migration as well as energy production and availability. In normal conditions, a dynamic interplay is established among mammalian cells and ECM, surrounding them. The result of this cooperation is the maintenance of a proper ECM composition, morphology, disposition and activity in all tissues and a correct intracellular structure and function, both in the cytoplasm and in micro-organelles, such as nucleus. In the last years, a large series of studies are focusing on a better understanding of ECM alterations and abnormalities, that emerge in its structure, shape and spatial organization, during the occurrence of different pathological conditions, such as inflammation and cancer. 3) ECM contributes to regulate and modulate a wide series of distinct cell activities, such as differentiation, apoptosis, proliferation, and migration as well as energy production and availability. In normal conditions, a dynamic interplay is established among mammalian cells and ECM, surrounding them. It involves soluble factors, such as chemokines, cytokines, costimulatory molecules, additional biological me