The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.

Targeting the Versatile Wnt/ß-Catenin Pathway in Cancer Biology and Therapeutics: From Concept to Actionable Strategy.

This expert review offers a critical synthesis of the latest insights and approaches at targeting the Wnt/ß-catenin pathway in various cancers such as colorectal cancer, melanoma, leukemia, and breast and lung cancers. Notably, from organogenesis to cancer, the Wnt/ß-catenin signaling displays varied and highly versatile biological functions in animals, with virtually all tissues requiring the Wnt/ß-catenin signaling in one way or the other. Aberrant expression of the members of the Wnt/ß-catenin has been implicated in many pathological conditions, particularly in human cancers. Mutations in the Wnt/ß-catenin pathway genes have been noted in diverse cancers. Biochemical and genetic data support the idea that inhibition of Wnt/ß-catenin signaling is beneficial in cancer therapeutics. The interaction of this important pathway with other signaling systems is also noteworthy, but remains as an area for further research and discovery. In addition, formation of different complexes by components of the Wnt/ß-catenin pathway and the precise roles of these complexes in the cytoplasmic milieu are yet to be fully elucidated. This article highlights the latest medical technologies in imaging, single-cell omics, use of artificial intelligence (e.g., machine learning techniques), genome sequencing, quantum computing, molecular docking, and computational softwares in modeling interactions between molecules and predicting protein-protein and compound-protein interactions pertinent to the biology and therapeutic value of the Wnt/ß-catenin signaling pathway. We discuss these emerging technologies in relationship to what is currently needed to move from concept to actionable strategies in translating the Wnt/ß-catenin laboratory discoveries to Wnt-targeted cancer therapies and diagnostics in the clinic.

Three-Dimensional Organoids in Cancer Research: The Search for the Holy Grail of Preclinical Cancer Modeling.

Most solid tumors become therapy resistant and will relapse, with no durable treatment option available. One major impediment to our understanding of cancer biology and finding innovative approaches to cancer treatment stems from the lack of better preclinical tumor models that address and explain tumor heterogeneity and person-to-person differences in therapeutic and toxic responses. Past cancer research has been driven by inadequate in vitro assays utilizing two-dimensional monolayers of cancer cells and animal models. Additionally, animal models do not truly mimic the original human tumor, are time consuming, and usually costly. New preclinical models are needed for innovation in cancer translational research. Hence, it is time to welcome the three-dimensional (3D) organoids: self-organizing cells grown in 3D culture systems mimicking the parent tissues from which the primary cells originate. The 3D organoids offer deeper insights into the crucial cellular processes in tissue and organ formation and pathological processes. Generation of near-perfect physiological microenvironments allow 3D organoids to couple with gene editing tools, such as the clustered regularly interspersed short palindromic repeat (CRISPR)/CRISPR-associated 9 and the transcription activator-like effector nucleases to model human diseases, offering distinct advantages over current models. We explain in this expert review that through recapitulating patients' normal and tumor tissues, organoid technology can markedly advance personalized medicine and help reveal once hidden aspects of cancers. The use of defined tissue- or organ-specific matrices, among other factors, will likely allow organoid technology to realize its potential in innovating many fields of life sciences.