The collection of chapters in this proceeding volume reflects the latest research presented at the Aegean meeting on Tumor Microenvironment and Cellular Stress held in Crete in Fall of 2012. The book provides critical insight to how the tumor microenvironment affects tumor metabolism, cell stemness, cell viability, genomic instability and more. Additional topics include identifying common pathways that are potential candidates for therapeutic intervention, which will stimulate collaboration between groups that are more focused on elucidation of biochemical aspects of stress biology and groups that study the pathophysiological aspects of stress pathways or engaged in drug discovery.

This volume covers the topics presented at the 3rd International Conference on Tumor Microenvironment and Cellular Stress by an international community of researchers. The conference brings together scientists to discuss different cellular and animal models of tumor microenvironment study and identify common pathways that are candidates for therapeutic intervention; stimulate collaboration between groups that are more focused on elucidation of biochemical aspects of stress biology (e.g., HIF regulation) and groups that study the pathophysiological aspects of stress pathways or engaged in drug discovery; and critically evaluate novel targets for imaging or therapeutic intervention that would be of use to the tumor microenvironment community and pharmaceutical industry.

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.

Over the past decade, the tumor microenvironment has become one of the most important research areas in cancer biology, as cells within the tumor microenvironment, despite being outnumbered by healthy cells, are able to evade surveillance and immune-mediated destruction. While researchers have learned a great deal about the cellular and structural makeup of the tumor microenvironment, there has been a growing understanding of the metabolic interplay between the tumor micronenvironment’s various cellular constituents and how each of them contributes to overall tumor growth and metastases. This new volume will guide researchers, students, oncologists and academics through a rapidly developing and changing field with a thorough understanding of tumor microenvironment biology from a cellular, structural, metabolic, and immunological perspective.

The microenvironment in which a tumor originates plays a critical role in its initiation and progression. Tumor Microenvironment reviews the importance of tumor microenvironment in cancer management. Particular emphasis is placed on discussing how the unique characteristics of the tumor microenvironment not only impact disease progression and response to conventional anticancer therapies, but have also led to the identification of potential new therapeutic targets and treatment possibilities for cancer patients. Tumor Microenvironment also reviews the fundamental basis of target development, preclinical assessment, and the current clinical status of these therapies.

This volume discusses recent research advances in cancer biology, focusing on the role of the tumor microenvironment. Taken alongside its companion volumes, Tumor Microenvironment: Recent Advances covers the latest research on various aspects of the tumor microenvironment, as well as future directions. Useful for introducing the newer generation of researchers to the history of how scientists studied the tumor microenvironment as well as how this knowledge is currently applied for cancer treatments, it will be essential reading for advanced cell biology and cancer biology students, as well as researchers seeking an update on research on the tumor microenvironment.

The fact that tumors are composed of both tumor cells and host cells has long been known. These tumor-associated cells include vascular endothelial cells and pe- cytes, as well as inflammatory cells such as neutrophils, monocytes, macrophages, mast cells and eosinophils, and lymphocytes. The tumor cells also interact with stromal cells and with elements of the tissue extracellular matrix. What has been less appreciated is the role that these cells could have in modulating the growth, invasion, and metastasis of the tumor. Early on, the elements of what we now call the tumor microenvironment were considered to be more or less innocent bysta- ers to the role of the tumor cells as they grew and invaded local sites. Today, there is an increased understanding of the critical role of the tumor microenvironment as dramatically influencing the course of tumor development and dissemination. This volume represents a superb compilation of the latest thoughts and data regarding the role of each essential component of the tumor microenvironment in cancer development and progression. Perhaps, the earliest recognition of the role of nonmalignant cells as cancer re- lators was the recognition that lymphocytes can participate in what was termed “immune surveillance” in the 1960s. Our understanding of tumor immunity has improved markedly since then, and there are now successful clinical studies sh- ing the potential use of immune-based therapies in cancer treatment.

Oncogenes and tumor suppressor genes had been traditionally studied in the context of cell proliferation, differentiation, senescence, and survival, four relatively cell-autonomous processes. Consequently, in the late ’80s-early ’90s, neoplastic growth was described largely as an imbalance between net cell accumulation and loss, brought about through mutations in cancer genes. In the last ten years, a more holistic understanding of cancer has slowly emerged, stressing the importance of interactions between neoplastic and various stromal components: extracellular matrix, basement membranes, fibroblasts, endothelial cells of blood and lymphatic vessels, tumor-infiltrating lymphocytes, etc. The commonly held view is that changes in tumor microenvironment are “soft-wired”, i.e., epigenetic in nature and often reversible. Yet, there exists a large body of evidence suggesting that well-known mutations in cancer genes profoundly affect tumor milieu. In fact, these non-cell-autonomous changes might be one of the primary reasons such mutations are preserved in late-stage tumors.

This volume discusses novel concepts in cancer biology, focusing on different factors that affect the tumor microenvironment. Topics covered include sex-based differences in the tumor microenironment, dormancy in the tumor microenvironment, the influence of obesity on the tumor microenvironment, and much more. Taken alongside its companion volumes, Tumor Microenvironment: Novel Concepts covers the latest research on various aspects of the tumor microenvironment, as well as future directions. Useful for introducing the newer generation of researchers to the history of how scientists studied the tumor microenvironment as well as how this knowledge is currently applied for cancer treatments, it will be essential reading for advanced cell biology and cancer biology students, as well as researchers seeking an update on research on the tumor microenvironment.

A link between inflammation and cancer has been established many years ago, yet it is only recently that the potential significance of this connection has become apparent. Although several examples of chronic inflammatory conditions, often induced by persistent irritation and/or infection, developing into cancer have been known for some time, there has been a notable resistance to contemplate the possibility that this association may apply in a causative way to other cancers. Examples for such progression from chronic inflammation to cancer are colon carcinoma developing with increased frequency in patients with ulcerative colitis, and the increased incidence of bladder cancer in patients suffering from chronic Schistosoma infection. Inflammation and cancer have been recognized to be linked in another context for many years, i.e., with regards to pathologies resembling chronic lacerations or 'wounds that do not heal.' More recently, the immunology of wound healing has given us clues as to the mechanistic link between inflammation and cancer, in as much as wounds and chronic inflammation turn off local cell-mediated immune responses and switch on growth factor release as well the growth of new blood vessels - angiogenesis. Both of these are features of most types of tumours, which suggest that tumours may require an immunologically shielded milieu and a growth factor-rich environment.