Reflected stemness as a potential driver of the tumour microenvironment

The tumorigenic potential of preneoplastic cells arises from the ability of genetic mutations in stem/progenitor cells to hijack tissue stemness and change their surrounding tissue. Preneoplastic cells depend on the acquisition of developmental programmes to initiate tumour growth, but the events required for their gain in tumorigenic potential are largely uncharacterised. We suggest that focusing on the early interaction between stem cells harbouring mutations in cancer-driver genes and the surrounding tissue cells, which might also carry genetic mutations, might hold the key to this understanding. Malignant stemness is not only necessary to sustain persistent growth and generate the entire heterogenicity of the tumour but also to modify the local microenvironment to generate an immunosuppressive and protumorigenic niche. Cancer cells trigger the activation of stemness programmes in the surrounding non-mutated cells. We speculate that this process may be needed for the initial reprogramming that drives the generation of the variety of cells of the tumour microenvironment. We propose that the ability of cancer cells to instigate stemness in the surrounding healthy tissue may foster regenerative pathways in cancer cells, leading to enhancement of their stemness programme and triggering a vicious cycle where malignant stemness is not only sustained but is also progressively amplified. A fundamental requirement for cancer initiation is the activation of developmental programmes by mutant cells. Oncogenic signals often confer an undifferentiated, stem cell-like phenotype that supports the long-term proliferative potential of cancer cells. Although cancer is a genetically driven disease, mutations in cancer-driver genes alone are insufficient for tumour formation, and the proliferation of cells harbouring oncogenic mutations depends on their microenvironment. In this Opinion article we discuss how the reprogrammed status of cancer cells not only represents the essence of their tumorigenicity but triggers 'reflected stemness' in their surrounding normal counterparts. We propose that this reciprocal interaction underpins the establishment of the tumour microenvironment (TME). A fundamental requirement for cancer initiation is the activation of developmental programmes by mutant cells. Oncogenic signals often confer an undifferentiated, stem cell-like phenotype that supports the long-term proliferative potential of cancer cells. Although cancer is a genetically driven disease, mutations in cancer-driver genes alone are insufficient for tumour formation, and the proliferation of cells harbouring oncogenic mutations depends on their microenvironment. In this Opinion article we discuss how the reprogrammed status of cancer cells not only represents the essence of their tumorigenicity but triggers 'reflected stemness' in their surrounding normal counterparts. We propose that this reciprocal interaction underpins the establishment of the tumour microenvironment (TME). the heterogeneous pool of activated fibroblasts within a cancerous tissue. a biological process in which cells become less specialised and return to a more primitive stage within the same lineage. the stemness of pluripotent stem cells – primordial undifferentiated cells that can self-renew and give rise to progenitors of the three primary germ layers: ectoderm, endoderm, and mesoderm. a developmental programme in which epithelial cells undergo a variety of biochemical alterations, such as loss of cell polarity and gain of invasive properties, to acquire a mesenchymal phenotype. the ability to maintain tissue integrity and function at steady-state. In a tissue at homeostasis, tissue stemness will maintain a steady balance between quiescence, self-renewal, and differentiation. normal tissue cells surrounding the cancer cells. the ability of cancer cells to display stem-like properties and unrestrained stemness which enables a constant high-rate of generation of progeny both with the same properties (self-renewal) and with other characteristics. It is distinct from normal tissue stemness because of the lack of regulatory ability to return to the resting status found at homeostasis. Malignant stemness is constantly amplified and active, leading to an ever-evolving cancer that lacks a resting homeostatic status. a stem cell with a genetic mutation which alters its stemness behaviour in favour of self-renewal, leading to its expansion in the tissue. Typically, mutations in oncogenes or tumour-suppressor genes can unleash uncontrolled stemness. Mutated stem cells can generate preneoplastic clones. molecular and phenotypic changes that allow cells to adopt different states or identities. clusters of cells that expand due to oncogene mutations which might lead to the malignant stemness potential needed for tumour initiation. cells that are descendents of stem cells and that can differentiate and give rise to one or more type of cells. defines a reversible state of inactivity or dormancy in which cells do not actively divide but maintain the capacity to re-enter cell proliferation. the phenomenon where cancer cells with malignant stemness induce a stem-like behaviour in the surrounding healthy epithelial tissue. the specific microenvironment supporting stemness in stem cells. This may include neighbouring epithelial cells, mesenchymal cells, and a particular extracellular matrix (ECM) protein composition. refers to molecular processes that underlie the fundamental properties of a cell to self-renew and give rise both to progeny with its same properties and to other differentiated cells of the tissue. an undifferentiated cell within a tissue that retains stemness. In an epithelial tissue, epithelial stem cells have multilineage potential to give rise to all the epithelial lineages of the organ. refers to tissue stem cells within their stem cell niche which together coordinate the ability of the tissue to maintain homeostasis and regenerate upon injury. the specific microenvironment that supports malignant, uncontrolled stemness in cancer cells. This generally includes perturbed mesenchymal cells and particular ECM components, but can also extend to include other cell types such as myeloid cells and neighbouring epithelial cells. the cellular and extracellular environment in which cancer cells exist; it is constituted by locally and systemically recruited non-cancer cells in the tumour structure, soluble factors, and ECM components.