Cancer Cell
Previews Huh, I., Zeng, J., Park, T., and Yi, S.V. (2013). Epigenetics Chromatin 6, 9.
Shenker, N., and Flanagan, J.M. (2012). Br. J. Cancer 106, 248–253.
B.A., Stamatoyannopoulos, J.A., Crawford, G.E., et al. (2013). Genome Res. 23, 555–567.
Jones, P.A. (2012). Nat. Rev. Genet. 13, 484–492.
Tran, R.K., Henikoff, J.G., Zilberman, D., Ditt, R.F., Jacobsen, S.E., and Henikoff, S. (2005). Curr. Biol. 15, 154–159.
Yang, X., Han, H., De Carvalho, D.D., Lay, F.D., Jones, P.A., and Liang, G. (2014). Cancer Cell 26, this issue, 577–590.
Varley, K.E., Gertz, J., Bowling, K.M., Parker, S.L., Reddy, T.E., Pauli-Behn, F., Cross, M.K., Williams,
Zilberman, D., Coleman-Derr, D., Ballinger, T., and Henikoff, S. (2008). Nature 456, 125–129.
Maunakea, A.K., Nagarajan, R.P., Bilenky, M., Ballinger, T.J., D’Souza, C., Fouse, S.D., Johnson, B.E., Hong, C., Nielsen, C., Zhao, Y., et al. (2010). Nature 466, 253–257.
Reprogramming the Tumor Stroma: A New Paradigm David R. Rowley1,* 1Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2014.09.016
A recent article in Cell shows that vitamin D receptor activation reprograms reactive stroma in the tumor microenvironment to a less inflammatory, quiescent state and is associated with increased drug retention, tumor response, and survival in pancreatic cancer models. Stroma reprogramming, as opposed to ablation, may emerge as a new treatment paradigm. It has been known for some time that carcinomas are associated with a reactive stroma microenvironment (RønnovJessen et al., 1996). Reactive stroma usually initiates early in cancer progression, co-evolves with the cancer, and represents a host response to disrupted epithelial homeostasis. In effect, the reactive stroma response is a rather generic response, ostensibly to serve a repair-centric function. The persistence of this response is what is observed in fibrosis disorders and during cancer progression. Less clear are the specific cell types, their origins, and how the biology of reactive stroma affects tumor progression. Collectively, this reactive stroma has been referred to as carcinoma-associated fibroblasts, myofibroblasts, or stellate cells (Apte et al., 2004; Orimo and Weinberg, 2006; Vonlaufen et al., 2008). The majority of studies have shown that reactive stroma generaly promotes tumors, yet specific mechanisms are not understood. The biology affected by the stromal compartment in cancer is likely to be quite complex and involve a balance among tumor-promoting and tumor-inhibiting mechanisms. Nevertheless, the notion of targeting the reactive stroma within the tumor microenvironment as a means
of inhibiting cancer progression is an attractive one. Perhaps one of the most important perspectives regarding reactive stroma was noted by Dvorak years ago, that cancers are like ‘‘wounds that do not heal’’ (Dvorak, 1986). The biology of wound repair is very complicated and is characterized by pro-growth conditions that require reactive stromal cells, followed by a return to a normal differentiation state. This process involves a resolution of the reactive, pro-growth repair state to one of more normal tissue quiescence and biology. Hence, stromal reprogramming is a part of normal wound repair biology. If, as Dvorak pointed out, cancers are like wounds that do not heal, then it can be surmised that the stromal reprogramming that instructs the stroma back to differentiation during wound repair simply does not normally occur in cancer. Considerable evidence in the literature supports this concept, which is well outlined by Sherman et al. (2014) in a recent issue of Cell. As aptly pointed out in this article, in addition to tumor-promoting functions, the persistent stromal response has also been shown to inhibit effective drug delivery and influence patterns of therapeutic resistance in pancreatic cancer.
Sherman et al. (2014) show that the vitamin D receptor (VDR) is a critical regulator of pancreatic stellate cells, the reactive stroma observed in pancreatic cancer. Importantly, this study shows that VDR activation results in a reprogramming of reactive stroma and reduced inflammatory markers typically associated with fibrosis. In pancreatic tumor models, this VDR-mediated stromal reprogramming resulted in increased drug (gemcitabine) availability and reduced tumor volume. Remarkably, use of the VDR ligand resulted in a 57% increase in animal survival as compared to gemcitabine treatment only. Effectively, this study suggests that VDR activation resolves the reactive stroma phenotype to one that is noninflammatory and quiescent. In essence, a reprogramming of the stroma to a state more common of normal homeostasis, such as would occur naturally during completion of normal wound healing. In this regard, it would seem that VDR activation in pancreatic cancer changes the tumor’s status from being a wound that does not heal, as cited by Dvorak, to a wound that is partially healed in the important stromal compartment. The overall importance of the Sherman et al. (2014) study is underscored by the
Cancer Cell 26, October 13, 2014 ª2014 Elsevier Inc. 451
Cancer Cell
Previews suggestion that ‘‘Vitamin D priming’’ may be an important adjuvant in the treatment of pancreatic cancer via enabling chemotherapeutic response as a result of stromal reprogramming. Ablation of reactive stroma or complete inhibition of reactive stroma formation has previously been suggested as a way to inhibit cancer progression. However, recent studies suggest that ablation of reactive stroma may not be very effective in treating pancreatic cancer (Amakye et al., 2013; O¨zdemir et al., 2014; Rhim et al., 2014). In addition, this ablationcentric paradigm may neither be easily attainable in patients nor the most natural way to modulate or resolve stromal reactions. The important new paradigm that evolves from the Sherman et al. (2014) study is the perspective that a reprogramming switch in the biology of
reactive stroma may be a more effective way to ensure efficient drug delivery and inhibit chemotherapeutic resistance mechanisms. Not only was this reprogramming attainable, it was achieved by activating a native VDR with an analog ligand, a rather natural approach. These seminal observations are truly paradigm shifting and may change the way we think about targeting the tumor microenvironment in order to influence cancer progression.
Dvorak, H.F. (1986). N. Engl. J. Med. 315, 1650– 1659. Orimo, A., and Weinberg, R.A. (2006). Cell Cycle 5, 1597–1601. O¨zdemir, B.C., Pentcheva-Hoang, T., Carstens, J.L., Zheng, X., Wu, C.C., Simpson, T.R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S.V., et al. (2014). Cancer Cell 25, 719–734. Rhim, A.D., Oberstein, P.E., Thomas, D.H., Mirek, E.T., Palermo, C.F., Sastra, S.A., Dekleva, E.N., Saunders, T., Becerra, C.P., Tattersall, I.W., et al. (2014). Cancer Cell 25, 735–747. Rønnov-Jessen, L., Petersen, O.W., and Bissell, M.J. (1996). Physiol. Rev. 76, 69–125.
REFERENCES Amakye, D., Jagani, Z., and Dorsch, M. (2013). Nat. Med. 19, 1410–1422.
Sherman, M.H., Yu, R.T., Engle, D.D., Ding, N., Atkins, A.R., Tiriac, H., Collisson, E.A., Connor, F., Van Dyke, T., Kozlov, S., et al. (2014). Cell 159, 80–93.
Apte, M.V., Park, S., Phillips, P.A., Santucci, N., Goldstein, D., Kumar, R.K., Ramm, G.A., Buchler, M., Friess, H., McCarroll, J.A., et al. (2004). Pancreas 29, 179–187.
Vonlaufen, A., Joshi, S., Qu, C., Phillips, P.A., Xu, Z., Parker, N.R., Toi, C.S., Pirola, R.C., Wilson, J.S., Goldstein, D., and Apte, M.V. (2008). Cancer Res. 68, 2085–2093.
NOTch Just a Bladder Control Problem Keli Xu,1 Darius J. Ba¨gli,2 and Sean E. Egan2,3,* 1Tumor
Cell Biology Program, Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada 3Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2014.09.018 2Program
Human bladder cancers harbor deletions and point mutations in genes coding for Notch receptors and proteins involved in Notch signaling. This leads to elevated MAPK pathway activation, as direct Notch-mediated transcription of MAPK phosphatase DUSP is lost. These bladder tumors, with impaired Notch signaling, also show basal differentiation. Bladder cancer, a common tumor associated with smoking, causes approximately 150,000 deaths worldwide each year. The vast majority of these tumors are derived from urothelium, a stratified epithelial structure lining the urineexposed surface of the bladder. A number of distinct bladder tumor types have been characterized, including papillary urothelial carcinomas, which are usually low-grade/localized lesions with excellent prognosis, as well as carcinoma in situ (CIS) and muscle-invasive urothelial carcinomas. Squamous cell carcinomas (SCCs) also represent a significant, but variable, fraction of bladder
cancers. Indeed, SCCs typically represent less than 5% of total bladder cancer cases; however, schistosomiasis infections or irritation and inflammation associated with frequent catheter use can increase the incidence of this disease. Interestingly, two groups used lineagetracing in a BBN [N-butyl-N-(4-hydroxybutyl)nitrosamine]-induced mouse model of bladder cancer to identify the cell of origin for most bladder cancers (Shin et al., 2014; Van Batavia et al., 2014). For example, Van Batavia et al. found that papillary tumors derive from intermediate layer epithelial progenitor cells, whereas flat aggressive lesions like CIS,
452 Cancer Cell 26, October 13, 2014 ª2014 Elsevier Inc.
muscle-invasive tumors, and SCC of the bladder arise through transformation of cytokeratin 5/p63-expressing cells in the basal layer (Van Batavia et al., 2014). Shin et al. showed that basal cells, which also express Shh, are absolutely required for CIS and invasive tumor formation (Shin et al., 2014). Surprisingly, muscle-invasive tumors form at the expense of SCC in Trp53 heterozygous mutant mice (Van Batavia et al., 2014). Over the past several years, a number of groups have reported on efforts to define the mRNA and microRNA gene expression profiles and proteomic profiles as well as the mutations,
Previews Huh, I., Zeng, J., Park, T., and Yi, S.V. (2013). Epigenetics Chromatin 6, 9.
Shenker, N., and Flanagan, J.M. (2012). Br. J. Cancer 106, 248–253.
B.A., Stamatoyannopoulos, J.A., Crawford, G.E., et al. (2013). Genome Res. 23, 555–567.
Jones, P.A. (2012). Nat. Rev. Genet. 13, 484–492.
Tran, R.K., Henikoff, J.G., Zilberman, D., Ditt, R.F., Jacobsen, S.E., and Henikoff, S. (2005). Curr. Biol. 15, 154–159.
Yang, X., Han, H., De Carvalho, D.D., Lay, F.D., Jones, P.A., and Liang, G. (2014). Cancer Cell 26, this issue, 577–590.
Varley, K.E., Gertz, J., Bowling, K.M., Parker, S.L., Reddy, T.E., Pauli-Behn, F., Cross, M.K., Williams,
Zilberman, D., Coleman-Derr, D., Ballinger, T., and Henikoff, S. (2008). Nature 456, 125–129.
Maunakea, A.K., Nagarajan, R.P., Bilenky, M., Ballinger, T.J., D’Souza, C., Fouse, S.D., Johnson, B.E., Hong, C., Nielsen, C., Zhao, Y., et al. (2010). Nature 466, 253–257.
Reprogramming the Tumor Stroma: A New Paradigm David R. Rowley1,* 1Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2014.09.016
A recent article in Cell shows that vitamin D receptor activation reprograms reactive stroma in the tumor microenvironment to a less inflammatory, quiescent state and is associated with increased drug retention, tumor response, and survival in pancreatic cancer models. Stroma reprogramming, as opposed to ablation, may emerge as a new treatment paradigm. It has been known for some time that carcinomas are associated with a reactive stroma microenvironment (RønnovJessen et al., 1996). Reactive stroma usually initiates early in cancer progression, co-evolves with the cancer, and represents a host response to disrupted epithelial homeostasis. In effect, the reactive stroma response is a rather generic response, ostensibly to serve a repair-centric function. The persistence of this response is what is observed in fibrosis disorders and during cancer progression. Less clear are the specific cell types, their origins, and how the biology of reactive stroma affects tumor progression. Collectively, this reactive stroma has been referred to as carcinoma-associated fibroblasts, myofibroblasts, or stellate cells (Apte et al., 2004; Orimo and Weinberg, 2006; Vonlaufen et al., 2008). The majority of studies have shown that reactive stroma generaly promotes tumors, yet specific mechanisms are not understood. The biology affected by the stromal compartment in cancer is likely to be quite complex and involve a balance among tumor-promoting and tumor-inhibiting mechanisms. Nevertheless, the notion of targeting the reactive stroma within the tumor microenvironment as a means
of inhibiting cancer progression is an attractive one. Perhaps one of the most important perspectives regarding reactive stroma was noted by Dvorak years ago, that cancers are like ‘‘wounds that do not heal’’ (Dvorak, 1986). The biology of wound repair is very complicated and is characterized by pro-growth conditions that require reactive stromal cells, followed by a return to a normal differentiation state. This process involves a resolution of the reactive, pro-growth repair state to one of more normal tissue quiescence and biology. Hence, stromal reprogramming is a part of normal wound repair biology. If, as Dvorak pointed out, cancers are like wounds that do not heal, then it can be surmised that the stromal reprogramming that instructs the stroma back to differentiation during wound repair simply does not normally occur in cancer. Considerable evidence in the literature supports this concept, which is well outlined by Sherman et al. (2014) in a recent issue of Cell. As aptly pointed out in this article, in addition to tumor-promoting functions, the persistent stromal response has also been shown to inhibit effective drug delivery and influence patterns of therapeutic resistance in pancreatic cancer.
Sherman et al. (2014) show that the vitamin D receptor (VDR) is a critical regulator of pancreatic stellate cells, the reactive stroma observed in pancreatic cancer. Importantly, this study shows that VDR activation results in a reprogramming of reactive stroma and reduced inflammatory markers typically associated with fibrosis. In pancreatic tumor models, this VDR-mediated stromal reprogramming resulted in increased drug (gemcitabine) availability and reduced tumor volume. Remarkably, use of the VDR ligand resulted in a 57% increase in animal survival as compared to gemcitabine treatment only. Effectively, this study suggests that VDR activation resolves the reactive stroma phenotype to one that is noninflammatory and quiescent. In essence, a reprogramming of the stroma to a state more common of normal homeostasis, such as would occur naturally during completion of normal wound healing. In this regard, it would seem that VDR activation in pancreatic cancer changes the tumor’s status from being a wound that does not heal, as cited by Dvorak, to a wound that is partially healed in the important stromal compartment. The overall importance of the Sherman et al. (2014) study is underscored by the
Cancer Cell 26, October 13, 2014 ª2014 Elsevier Inc. 451
Cancer Cell
Previews suggestion that ‘‘Vitamin D priming’’ may be an important adjuvant in the treatment of pancreatic cancer via enabling chemotherapeutic response as a result of stromal reprogramming. Ablation of reactive stroma or complete inhibition of reactive stroma formation has previously been suggested as a way to inhibit cancer progression. However, recent studies suggest that ablation of reactive stroma may not be very effective in treating pancreatic cancer (Amakye et al., 2013; O¨zdemir et al., 2014; Rhim et al., 2014). In addition, this ablationcentric paradigm may neither be easily attainable in patients nor the most natural way to modulate or resolve stromal reactions. The important new paradigm that evolves from the Sherman et al. (2014) study is the perspective that a reprogramming switch in the biology of
reactive stroma may be a more effective way to ensure efficient drug delivery and inhibit chemotherapeutic resistance mechanisms. Not only was this reprogramming attainable, it was achieved by activating a native VDR with an analog ligand, a rather natural approach. These seminal observations are truly paradigm shifting and may change the way we think about targeting the tumor microenvironment in order to influence cancer progression.
Dvorak, H.F. (1986). N. Engl. J. Med. 315, 1650– 1659. Orimo, A., and Weinberg, R.A. (2006). Cell Cycle 5, 1597–1601. O¨zdemir, B.C., Pentcheva-Hoang, T., Carstens, J.L., Zheng, X., Wu, C.C., Simpson, T.R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S.V., et al. (2014). Cancer Cell 25, 719–734. Rhim, A.D., Oberstein, P.E., Thomas, D.H., Mirek, E.T., Palermo, C.F., Sastra, S.A., Dekleva, E.N., Saunders, T., Becerra, C.P., Tattersall, I.W., et al. (2014). Cancer Cell 25, 735–747. Rønnov-Jessen, L., Petersen, O.W., and Bissell, M.J. (1996). Physiol. Rev. 76, 69–125.
REFERENCES Amakye, D., Jagani, Z., and Dorsch, M. (2013). Nat. Med. 19, 1410–1422.
Sherman, M.H., Yu, R.T., Engle, D.D., Ding, N., Atkins, A.R., Tiriac, H., Collisson, E.A., Connor, F., Van Dyke, T., Kozlov, S., et al. (2014). Cell 159, 80–93.
Apte, M.V., Park, S., Phillips, P.A., Santucci, N., Goldstein, D., Kumar, R.K., Ramm, G.A., Buchler, M., Friess, H., McCarroll, J.A., et al. (2004). Pancreas 29, 179–187.
Vonlaufen, A., Joshi, S., Qu, C., Phillips, P.A., Xu, Z., Parker, N.R., Toi, C.S., Pirola, R.C., Wilson, J.S., Goldstein, D., and Apte, M.V. (2008). Cancer Res. 68, 2085–2093.
NOTch Just a Bladder Control Problem Keli Xu,1 Darius J. Ba¨gli,2 and Sean E. Egan2,3,* 1Tumor
Cell Biology Program, Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada 3Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2014.09.018 2Program
Human bladder cancers harbor deletions and point mutations in genes coding for Notch receptors and proteins involved in Notch signaling. This leads to elevated MAPK pathway activation, as direct Notch-mediated transcription of MAPK phosphatase DUSP is lost. These bladder tumors, with impaired Notch signaling, also show basal differentiation. Bladder cancer, a common tumor associated with smoking, causes approximately 150,000 deaths worldwide each year. The vast majority of these tumors are derived from urothelium, a stratified epithelial structure lining the urineexposed surface of the bladder. A number of distinct bladder tumor types have been characterized, including papillary urothelial carcinomas, which are usually low-grade/localized lesions with excellent prognosis, as well as carcinoma in situ (CIS) and muscle-invasive urothelial carcinomas. Squamous cell carcinomas (SCCs) also represent a significant, but variable, fraction of bladder
cancers. Indeed, SCCs typically represent less than 5% of total bladder cancer cases; however, schistosomiasis infections or irritation and inflammation associated with frequent catheter use can increase the incidence of this disease. Interestingly, two groups used lineagetracing in a BBN [N-butyl-N-(4-hydroxybutyl)nitrosamine]-induced mouse model of bladder cancer to identify the cell of origin for most bladder cancers (Shin et al., 2014; Van Batavia et al., 2014). For example, Van Batavia et al. found that papillary tumors derive from intermediate layer epithelial progenitor cells, whereas flat aggressive lesions like CIS,
452 Cancer Cell 26, October 13, 2014 ª2014 Elsevier Inc.
muscle-invasive tumors, and SCC of the bladder arise through transformation of cytokeratin 5/p63-expressing cells in the basal layer (Van Batavia et al., 2014). Shin et al. showed that basal cells, which also express Shh, are absolutely required for CIS and invasive tumor formation (Shin et al., 2014). Surprisingly, muscle-invasive tumors form at the expense of SCC in Trp53 heterozygous mutant mice (Van Batavia et al., 2014). Over the past several years, a number of groups have reported on efforts to define the mRNA and microRNA gene expression profiles and proteomic profiles as well as the mutations,
