Abstract
Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value.
Highlights
It is widely recognized that tumor progression and metastasis are intimately linked to tissue remodeling resulting from tumor cell interactions with the host tissue stroma
Our results reveal distinct stromal gene expression signatures in human breast and prostate cancer, each of which is predictive of poor prognosis of its respective tumor type, and identify a small deregulated gene set common to both tumor types that, by contrast, is not predictive of patient survival
Normal and tumor tissue sections of the breast and prostate patients were subjected to laser capture microdissection (LCM) for selective analysis of the stromal compartment (Figure S2)
Summary
It is widely recognized that tumor progression and metastasis are intimately linked to tissue remodeling resulting from tumor cell interactions with the host tissue stroma. Activated macrophages and recruited leukocytes in turn secrete their own repertoire of cytokines, chemokines and proteolytic enzymes, leading to ECM degradation, which results in the release of a host of sequestered growth factors [7,8,9]. Some of these growth factors participate in promoting angiogenesis whereas others stimulate fibroblasts and myofibroblasts to synthesize and secrete ECM proteins [2,5,6]. The released growth factors and ECM degradation products provide resources that ensure tumor cell survival, proliferation and migration, which in turn perpetuate tissue remodeling, leading to the notion that invasive tumors behave as ‘‘wounds that never heal’’ [11]
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