Cell extrinsic consequences of epithelial stress: activation of pro-tumorigenic tissue phenotypes

Abstract Introduction Tumors are characterized by alterations in the epithelial and stromal compartments, which both contribute to tumor promotion. However, where, when, and how the tumor stroma develops is still poorly understood. We previously demonstrated that DNA damage or telomere malfunction induces an activin A-dependent epithelial stress response that activates cell-intrinsic and cell-extrinsic consequences in mortal, nontumorigenic human mammary epithelial cells (HMECs and vHMECs). Here we show that this epithelial stress response also induces protumorigenic phenotypes in neighboring primary fibroblasts, recapitulating many of the characteristics associated with formation of the tumor stroma (for example, desmoplasia). Methods The contribution of extrinsic and intrinsic DNA damage to acquisition of desmoplastic phenotypes was investigated in primary human mammary fibroblasts (HMFs) co-cultured with vHMECs with telomere malfunction (TRF2-vHMEC) or in HMFs directly treated with DNA-damaging agents, respectively. Fibroblast reprogramming was assessed by monitoring increases in levels of selected protumorigenic molecules with quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and immunocytochemistry. Dependence of the induced phenotypes on activin A was evaluated by addition of exogenous activin A or activin A silencing. In vitro findings were validated in vivo, in preinvasive ductal carcinoma in situ (DCIS) lesions by using immunohistochemistry and telomere-specific fluorescent in situ hybridization. Results HMFs either cocultured with TRF2-vHMEC or directly exposed to exogenous activin A or PGE2 show increased expression of cytokines and growth factors, deposition of extracellular matrix (ECM) proteins, and a shift toward aerobic glycolysis. In turn, these "activated" fibroblasts secrete factors that promote epithelial cell motility. Interestingly, cell-intrinsic DNA damage in HMFs induces some, but not all, of the molecules induced as a consequence of cell-extrinsic DNA damage. The response to cell-extrinsic DNA damage characterized in vitro is recapitulated in vivo in DCIS lesions, which exhibit telomere loss, heightened DNA damage response, and increased activin A and cyclooxygenase-2 expression. These lesions are surrounded by a stroma characterized by increased expression of α smooth muscle actin and endothelial and immune cell infiltration. Conclusions Thus, synergy between stromal and epithelial interactions, even at the initiating stages of carcinogenesis, appears necessary for the acquisition of malignancy and provides novel insights into where, when, and how the tumor stroma develops, allowing new therapeutic strategies

Complications of traditional Chinese/herbal medicines (TCM)—a guide for perplexed oncologists and other cancer caregivers

Introduction: Cancer patients often seek complementary or alternative medicines to supplement or replace treatments prescribed by licensed medical practitioners. Traditional Chinese/herbal medicine (TCM) is a popular complementary intervention among cancer patients of Asian ethnicity, many of whom take it during their conventional treatment. Few of these patients inform their doctors, however, creating a risk of unexpected sequelae arising from either pharmacologic toxicity, unsuitable dosing, interactions with anti-cancer drugs or other medications, adulteration, or idiosyncratic reactions. If unrecognized, these problems may be misattributed to conventional treatment toxicity or disease progression, and remedial action may be inappropriate or delayed. Goals of work: The purpose of this review is to help oncologists recognize the common presentations of TCM-related problems in cancer patients-such as abnormal liver function tests, unexpectedly severe myelosuppression, hemostatic defects, renal functional impairment, or suspected drug interactions-and to teach strategies by which these problems can be anticipated, prevented, or managed. Conclusion: Through sensitive understanding of the reasons favoring TCM usage, oncologists can gain the trust and respect of their TCM-using patients while ensuring the safety and efficacy of conventional anticancer treatments. © 2008 Springer-Verlag.link_to_subscribed_fulltex