Trends in Genetics
Volume 25, Issue 1, January 2009, Pages 30-38
Journal home page for Trends in Genetics

Review
Co-evolution of tumor cells and their microenvironment

https://doi.org/10.1016/j.tig.2008.10.012Get rights and content

Increasing evidence indicates that tumor–stromal cell interactions have a crucial role in tumor initiation and progression. These interactions modify cellular compartments, leading to the co-evolution of tumor cells and their microenvironment. Although the importance of microenvironmental alterations in tumor development is recognized, the molecular mechanisms underlying these changes are only now beginning to be understood. Epigenetic and gene expression changes have consistently been reported in cancer-associated stromal cells and the influence of the host genotype on tumorigenesis is also well documented. However, the presence of clonally selected somatic genetic alterations within the tumor microenvironment has been controversial. A thorough understanding of the co-evolution of these two cellular compartments will require carefully executed molecular studies combined with mathematical modeling.

Section snippets

Tumorigenesis is an evolutionary process

Natural selection and species evolution are the result of complex interactions among living organisms and their environment. Environmental alterations, together with natural variability in hereditary traits, continuously shape species. There are numerous examples of co-evolution of species, whereas the fitness of the ecosystem as a whole, rather than that of any particular individual species, drives selection. The tumorigenic process shares many similarities with the evolution of ecosystems;

The role of the microenvironment in tumorigenesis

Extensive data from patients and various animal and cell culture models have demonstrated widespread tumor–stromal cell interactions that influence tumorigenesis 3, 4, 5, 6, 7. Detailed molecular characterization of various cell types from normal breast tissue, ductal carcinoma in situ (DCIS) and invasive breast tumors has revealed that gene expression changes occur in all cell types during breast tumor progression [8]. Interestingly, a large fraction of the genes abnormally expressed in tumors

Can the microenvironment drive tumor initiation and progression?

In part building on these prior data, a provocative study proposed that the stroma is the crucial target of chemical carcinogen-induced mammary tumors and that mutations in epithelial cells are not sufficient for tumor initiation [16]. These conclusions were drawn based on the observation that mammary tumors developed only when rats were exposed to the mutagen N-nitrosomethyl urea (NMU), regardless of whether or not the injected mammary epithelial cells were NMU treated. A drawback of this

Targeting microenvironmental alterations in cancer prevention and treatment

Microenvironmental changes not only influence tumor progression, but they also dramatically influence the efficacy of cancer therapy. This is especially true for therapy that targets pathways regulated by extracellular signals, for example, angiogenesis and growth factor receptor pathways. The importance of stromal–epithelial paracrine interactions in cancer therapy was elegantly demonstrated in a recent study by Yauch and colleagues [10]. The hedgehog (Hh) signaling pathway has a key role in

The influence of the tumor on the host: is cancer a systemic disease?

In addition to local changes in the tumor microenvironment, several studies have raised the possibility that growing tumors induce systemic changes in the cancer-bearing host that might promote tumor growth and metastatic spread (Box 1). Paraneoplastic syndromes, symptoms caused by the presence of cancer in the body that are not due to the local effects of cancer cells, represent an example for tumor-induced systemic effects. One such symptom is the increased blood coagulation associated with

Somatic genetic alterations in cells comprising the tumor microenvironment

Although the importance of microenvironmental changes in tumorigenesis has conclusively been demonstrated, the mechanisms underlying such alterations in human cancer remain intensely debated. Cancer is a genetic disease; inherited or somatic alterations in key regulatory genes lead to cellular transformation and the subsequent accumulation of additional changes results in the full-blown malignant tumor cell phenotype [36]. Numerous studies have demonstrated extensive copy number alterations

Putative models of tumor–stromal cell co-evolution

Putting aside potential technical issues, several possible explanations could account for the presence of clonal genetic alterations in tumor-associated stromal cells. Some explanations might reflect stromal cell recruitment by the tumor and subsequent preferential stromal cell outgrowth (derived from a single progenitor cell) that supports overall tumor growth. Alternatively, they might represent a selection for mutant stromal cells that attempted to suppress tumor formation. Lastly, these

Epigenetic alterations in cells comprising the tumor microenvironment

Epigenetic programs including DNA methylation and chromatin modification patterns define cellular differentiation. Likewise, aberrant differentiation and associated abnormal cellular phenotypes are, in part, defined by abnormal epigenetic programs. The observation that molecular and functional differences between normal and cancer-associated fibroblasts are maintained even after removal of these cells from the tissue and after prolonged cell culture indicates that hereditary mechanisms underlie

Concluding remarks and future perspectives

Although the importance of an altered microenvironment in tumorigenesis is no longer disputed 3, 4, 5, 6, 7, the nature of the molecular alterations underlying these changes remains uncertain. The confusion that surrounds the presence of clonally selected somatic genetic alterations in cancer-associated stromal cells in human tumors should be resolved by comparative analyses of the same tumor samples both as frozen and FFPE tissue using multiple comprehensive methods. If these alterations truly

Acknowledgements

The authors thank members of their laboratories for their critical reading of the manuscript and constructive discussion. Work in the authors’ laboratory is supported by the National Cancer Institute (CA89393 and CA116235), Department of Defense (W81XWH-07–1-0294), American Cancer Society (RSG-05–154–01-MGO), Avon Foundation and Novartis Oncology grants awarded to K.P., and Department of Defense (W81XWH-04–1-0336, W81XWH-04–1-0609, W81XWH-06–1-0643 and W81XWH-06–0220), Australian NH and MRC

Glossary

Epithelial–mesenchymal transition (EMT)
a process by which epithelial cells can convert to mesenchymal cells. EMT is essential for the development of certain organs and in cancer it can contribute to tumor cell heterogeneity and metastatic progression.
Mesenchymal cells
in animals with three tissue germ layers, the mesoderm is the middle layer of tissue, lying between the ectoderm and the endoderm. Cells present and derived from the mesoderm are called mesenchymal cells. In contrast to epithelial

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