Abstract
Tissues contain multiple different cell types and can be considered to be heterocellular systems. Signaling between different cells allows tissues to achieve phenotypes that no cell type can achieve in isolation. Such emergent tissue-level phenotypes can be said to ‘supervene upon’ heterocellular signaling. It is proposed here that cancer is also an emergent phenotype that supervenes upon heterocellular signaling. Using colorectal cancer (CRC) as an example, I review how heterotypic cells differentially communicate to support emergent malignancy. Studying tumors as integrated heterocellular systems – rather than as solitary expansions of mutated cells – may reveal novel ways to treat cancer.
Highlights
Tissues contain multiple different cell types and can be considered to be heterocellular systems
tumor-associated macrophages (TAMs) play a major role in processing colorectal cancer (CRC) extracellular matrix (ECM), and can regulate collagen production by fibroblasts [43]
Myofibroblast abundance correlates with the increased presence of cytotoxic T cells in CRC [27]. This can result from fibroblast Toll-like receptor (TLR) activation, which upregulates proinflammatory cytokines that can recruit lymphocytes and myeloid cells into a tumor [54]
Summary
Tissues contain multiple different cell types and can be considered to be heterocellular systems. Cancer as an Emergent Heterocellular Phenotype Metazoan tissues are composed of multiple cell types (e.g., epithelial and mesenchymal cells, leukocytes) [1] and can be thought of as heterocellular systems (see Glossary) [2]. To the healthy colon, colorectal cancer (CRC) tumors contain epithelial cells, mesenchymal fibroblasts, myeloid cells, and lymphocytes [6]. This homocellular view ignores the explicit heterocellularity of metazoan biology Both in healthy and diseased tissue, colonic epithelia always interact with intestinal mesenchymal cells, lymphocytes, and myeloid cells. Each of these heterotypic cell types processes signals differently from epithelial cells, and can subsequently facilitate unique heterocellular phenotypes. Heterocellular emergence: a process where complex phenotypes are achieved through interactions between different cell types (e.g., adaptive immunity). Tumor microenvironment: all cells, matrix, and nutrients in the vicinity of a tumor
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