Molecules Of The Extracellular Matrix As Cancer Targets

Cancer was thought to originate from alterations in intercellular signaling that resulted in the transformation of cells, their uncontrolled proliferation and metastasis. There is now an increasing body of evidence demonstrating that the surrounding matrix and cell-matrix interactions are also major players in this process. Cells adhere and receive signals from various extracellular matrices via transmembrane receptors, the best known of which are the heterodimeric glycoproteins, integrins.

The extracellular matrix (ECM) scaffold, which surrounds and supports the cells in tissues, consists of fibrillar proteins, proteoglycans, glycosaminoglycans, signaling molecules, and enzymes involved in its remodeling. The stages of cancer progression, e.g., local invasion, intravasation, extravasation, distant invasion and immunosuppression, are obligatorily perpetrated through interactions of these tumor cells with the ECM. Cancer-related ECM changes can be exploited for the evaluation of disease progression, anticancer therapy development, and monitoring of therapy response. Thus, in breast cancer, hyaluronan-mediated wound repair mechanisms are hijacked to promote tumor development. Altered mechanical properties of the pancreatic cancer ECM are immunosuppressive and prevent the penetration of cytotoxic chemotherapy agents. The expression of the proteoglycan syndecan-4 is modulated by anticancer drugs, suggesting its potential druggabilty capacity. Another proteoglycan, lumican, is proposed as a cancer prognosis marker, chemoresistance regulator, and cancer therapy target. Due to their remodeling properties, the MMPs are vital mediators and important therapeutic targets. Treatment of breast cancer cells with sulfated hyaluronan has been shown to attenuate tumor cell growth, migration, and invasion. Extracellular vesicles (EVs), comprising exosomes, microvesicles, and apoptotic bodies, are released by all cells into the ECM and body fluids and can be utilized as diagnostic markers in malignant pleural mesothelioma. These exciting developments encourage tumor biology scientists for further creative research.

This publication presents a collection of essays that reflect current research and technical advances in extracellular matrix field, which has undergone remarkable expansion since publication of Volume 82 of 'Methods in Enzymology' in 1982.

Knowledge of the extracellular matrix (ECM) is essential to understand cellular differentiation, tissue development, and tissue remodeling. This volume of the series “Biology of Extracellular Matrix” provides a timely overview of the structure, regulation, and function of the major macromolecules that make up the extracellular matrix. It covers topics such as collagen types and assembly of collagen-containing suprastructures, basement membrane, fibronectin and other cell-adhesive glycoproteins, proteoglycans, microfibrils, elastin, fibulins and matricellular proteins, such as thrombospondin. It also explores the concept that ECM components together with their cell surface receptors can be viewed as intricate nano-devices that allow cells to physically organize their 3-D-environment. Further, the role of the ECM in human disease and pathogenesis is discussed as well as the use of model organisms in elucidating ECM function.

Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.

Most cancer deaths are a result of metastasis. The spread of a primary tumor to colonize neighboring and distant organs is the relentless endgame that defines the neoplastic process. Patients who have been diagnosed with cancer are treated to prevent both the recurrence of the tumor at the site of origin and metastasis that would re-stage them as advanced stage IV cancer. Historically and still with some types of cancer, stage IV is perceived by patients as “terminal.” Fortunately, recent molecular therapies have extended the lives of patients with advanced cancer and reassuringly people living with metastatic disease increasingly visit our clinics. What is the path forward? Given that the consilience of science and medicine is a dynamic art from which therapies arise, it would be misguided to consider any single work adequate at capturing the horizon for research. So with humility we constructed this text as primer for scientists. It begins with a broad introduction to the clinical management of common cancers. This is intended to serve as a foundation for investigators to consider when developing basic science hypotheses. Unquestionably, medical and surgical care of cancer patients reveals biology and dictates how novel therapeutics will ultimately be evaluated in clinical trials. The second section of this text offers provocative and evolving insights that underscore the breadth of science involved in the elucidation of cancer metastasis biology. The text concludes with information that integrates scientific and clinical foundations to highlight translational research. This book serves as a framework for scientists to conceptualize clinical and translational knowledge on the complexity of disease that is metastatic cancer.