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decreased risk of fibrosis in women compared to men, although higher levels of estrogen are a more likely determinant of protection from fibrosis in premenopausal women.
How relevant are these findings to human liver disease, and to what extent do transmissible parental epigenetic changes contribute to the overall risk of liver disease compared to germline polymorphisms? Are they equally important for all etiologies of hepatic fibrosis? The answers to these questions are neither known nor easily uncovered, but intuition would suggest that parental influences are relatively modest in adult liver diseases—yet they might be quite important
in fibrotic neonatal liver diseases whose causes remain unknown, for example biliary atresia11.
Finally, readers should be cautioned against assuming that parental liver disease is protective against risk of hepatic fibrosis in children, particularly in alcoholic liver disease where the propensity to abuse alcohol and the risk of injury have strong genetic components12. In this circumstance, the sins of the fathers are unlikely to mitigate those of their sons.
COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. 1. Hernandez-Gea, V. & Friedman, S.L. Annu. Rev. Pathol.
6, 425–456 (2011).
2. Weber, S., Gressner, O.A., Hall, R., Grunhage, F. & Lammert, F. Clin. Liver Dis. 12, 747–757 (2008).
3. Zeybel, M. et al. Nat. Med. 18, 1369–1377 (2012).4. Friedman, S.L. Nat. Rev. Gastroenterol. Hepatol. 7,
425–436 (2010).5. Relton, C.L. et al. PLoS One 7, e31821 (2012).6. Dietz, D.M. et al. Biol. Psychiatry 70, 408–414
335–343 (2010).12. Stickel, F. & Hampe, J. Gut 61, 150–159 (2012).
Figure 1 Paternal epigenetic suppression of hepatic fibrosis in male progeny via a transmissible factor. Liver injury in male rats leads to activation of hepatic stellate cells, the principal scar-producing cell type in liver. Zeybel et al.3 demonstrate that this fibrogenic response elicits the release of a transmissible factor that alters the epigenomes of sperm in the injured rat. When transmitted to their male progeny, these altered sperm confer a state of reduced stellate cell activation and attenuated liver fibrosis to the offspring that becomes apparent after liver injury. The findings point to an unexpected role of heritable epigenetic changes in modulating the fibrogenic response.
Liver injury Liver injury
Male F0
Liver fibrosis Epigenetic changes to sperm Reduced liver fibrosis
Transmissiblefactor(s)
Scar matrix
Hepatocytes
Activatedstellate cell
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H3K27me3 H2A.Z
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Pparg
The tumor microenvironment controls drug sensitivityArne Östman
A better understanding of mechanisms involved in regulation of drug sensitivity is crucial for improved cancer treatment. New studies show that cells of the tumor microenvironment modulate the response of cancer cells to chemotherapy and targeted therapies through production of secreted factors (pages 1359–1368).
Arne Östman is in the Department of Oncology-
Pathology, Karolinska Institutet, Stockholm, Sweden.
The goal for cancer research is to provide personalized and effective cancer treatments. An important part of these studies is to better
markers of drug sensitivity, already clinically implemented, include estrogen receptors, amplified human epidermal growth factor receptor 2 (HER2) and mutated epidermal growth factor receptor (EGFR) or BRAF, which guides the use of endocrine treatment and targeted therapies1–3. Other markers
understand the biological basis for variations in response to treatment, as well as to identify markers for drug sensitivity and resistance. The molecular determinants of sensitivity and primary or acquired resistance have traditionally been identified through characterization of the malignant target cells. Wellestablished
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identify resistance to treatment, such as RAS mutations that define a group of patients with colorectal cancer not susceptible to treatment with EGFRtargeting antibodies4. However, in spite of this progress it is clear that many aspects of drug sensitivity remain unknown.
The cells of the tumor microenvironment are increasingly recognized as major determinants of tumor biology5,6. Key cell types in this context are the cells of the tumor vasculature, fibroblasts and inflammatory cells, which commonly interact with the malignant cells through secreted factors mediating paracrine signaling. In addition to their impact on tumor growth, these cells have more recently also been shown to affect tumor initiation, cancer stem cells and metastasis. A study published in this issue of Nature Medicine7 and two other recent studies8,9 provide compelling evidence that the
tumor microenvironment is also an important regulator of cancercell drug sensitivity.
The new studies clearly demonstrate that drug responses of cancer cells are not exclusively determined by their intrinsic characteristics but are also controlled by signals derived from cells of the tumor microenvironment (Fig. 1). Importantly, the studies also suggest novel combination treatments that could eventually overcome this microenvironmentderived resistance.
The study by Sun et al.7 in this issue identifies WNT16B as an important stromaderived and treatmentinduced modulator of chemo therapy sensitivity. The starting point for this study was the identification of treatmentinduced transcriptional changes, including upregulation of WNT16B, in the stroma of human prostate cancer and in cultured fibroblasts.
Chemotherapyinduced upregulation of WNT16B protein was shown in the tumor stroma of prostate, breast and ovarian cancers. Mechanistically, nuclear factorκB (NFκB) was identified as a key component mediating WNT16B upregulation upon DNA damage caused by chemotherapy. The treatment protective effect of stromaderived WNT16B was deduced from cell culture experiments and in breast and prostate tumor xenograft models, indicating that WNT16B secreted by fibroblast reduces druginduced apoptosis in cancer cells. The study thus identifies WNT16B as a stromaderived regulator of drug response. The study uncovers new opportunities for combination treatments, including targeting of stromaderived WNT16B, which would eventually overcome this new resistance mechanism. Additionally, the findings also support the concept that chemotherapy and radiation treatment induce stromaderived resistance factors. This concept has also been promoted in two other recent studies of breast cancer models that strongly imply treatmentinduced tumor stroma changes as mechanisms that contribute to drug response10,11. Additionally, the findings also support the concept that chemo therapy and radiation treatment induce stromaderived resistance factors. The study uncovers new opportunities for combination treatments, including targeting of stroma derived WNT16B, which would eventually overcome this new resistance mechanism.
Two other recently published studies used cell culture analyses and supportive clinical data to provide independent evidence that paracrine signaling from cells of the tumor microenvironment can affect cancercell drug sensitivity8,9. Particularly, hepatocyte growth factor (HGF) produced by the tumor microenvironment reduced the sensitivity of melanoma cells to RAF inhibitors by activating MET receptors on the cancer cells. Straussman et al.8 found that high production of HGF by tumor stroma cells was associated with reduced response to RAF inhibitors, whereas Wilson et al.9 identified associations between circulating levels of HGF and survival among patients with melanoma treated with RAF inhibitors. In addition, the studies indicate that tumor microenviroment–induced modulation of sensitivity to targeted therapies also contri bute to drug sensitivity in other cancer settings, including HER2positive breast cancer and colorectal cancers with BRAF mutations. The studies thus have implications for many tumor types and different types of treatment.
The new studies7–9 substantiate earlier evidence suggesting stromaderived signaling as a crucial regulator of cancer cell response to chemotherapy, endocrine treatment and
Figure 1 Tumor microenvironment regulates drug sensitivity. Three studies7–9 show that secreted stroma-derived proteins can influence drug sensitivity of tumor cells. Sun et al.7 found that DNA damage caused by treatment with chemotherapeutic drugs induces WNT16B expression in stromal cells in prostate cancer (top). Secretion of WNT16B promoted tumor growth by activating Wnt signaling in cancer cells and reduced the chemotherapy sensitivity of experimental tumors, resulting in disease progression. Two related studies show that in tissue culture models of BRAF-mutated melanoma, HGF derived from the culture medium of stromal cells, or introduced as a recombinant protein, reduced the cancer cell sensitivity to BRAF inhibitors (bottom)8,9.
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targeted therapies. McMillin et al.12 showed that the sensitivity profile of myeloma cells, obtained in an in vitro drug screen, was largely affected by the presence of bone marrow stromal cells. Regarding endocrine treatment, it has been shown that factors secreted by cancerassociated fibroblasts, or extracellular matrix components, can alter the response of estrogen receptor–positive breast cancer cells to tamoxifen treatment13–15. Moreover, the in vitro sensitivity of head and neck squamous cell carcinoma cells and lung cancer cells to EGFR inhibitors has been shown to be regulated by cocultured fibroblasts16,17. Interestingly, HGF was also identified as one of the crucial fibroblastderived regulators of sensitivity in the lung cancer study.
Together with earlier findings, the three studies7–9 make a strong case for continued translational studies on the predictive roles of stromaderived factors. The analyses of clinical material in the new studies should be considered preliminary given the few number of cases analyzed. Additional studies on larger patient cohorts are thus warranted. Furthermore, future studies should also be designed so that they are able to separately analyze the prognostic and responsepredicative role of stromal WNT16B and HGF.
It is now increasingly recognized that markers expressed by malignant cells, including estrogen receptors and HER2, show some disconcordance between primary tumors and metastasis18. These findings emphasize
the need to obtain biopsies from metastatic lesions to make proper decisions on selection of treatment. The recent studies raise the issue on whether stromal markers show similar temporal and spatial instability. Future studies comparing stroma characteristics in matched primary tumor and metastases are thus crucial.
The new evidence also suggests opportunities for rational, and individualized, combination treatments. Some encouraging results in this context have already been provided with reports at the 2012 American Society of Clinical Oncology Annual Meeting showing the feasibility of combining BRAF and MEK inhibitors. On the basis of the Straussman and Wilson studies8,9, it can be hypothesized that this type of combination, or even combinations of BRAF inhibitors and HGF or MET inhibitors, will be particularly useful for individuals with BRAFmutated melanoma showing high expression of HGF in the tumor stroma. The identification by Sun et al.7 of a role of stromaderived WNT16B in prostate cancer also suggest continued translational studies. It would be interesting to compare the efficacies of specific WNT16B blockade and a more general inhibition of the stroma genotoxic response achieved through NFκB blockade. Given the multiple effects of NFκB, it is also relevant to perform comparative analyses of the effects of NFκB inhibition in malignant cells and in different cell types of the tumor microenvironment.
These studies set the stage for future research on interactions between cancer drug sensitivity and the tumor microenvironment. Development of methods for highcontent profiling of this complex biological landscape thus seems to be a very important task for future research.
COMPETING FINANCIAL INTERESTS The author declares no competing financial interests.
1. Flaherty, K.T. et al. N. Engl. J. Med. 363, 809–819 (2010).
2. Slamon, D.J. et al. N. Engl. J. Med. 344, 783–792 (2001).
3. Maemondo, M. et al. N. Engl. J. Med. 362, 2380–2388 (2010).
4. Amado, R.G. et al. J. Clin. Oncol. 26, 1626–1634 (2008).
5. Hanahan, D. & Coussens, L.M. Cancer Cell 21, 309–322 (2012).
6. Pietras, K. & Ostman, A. Exp. Cell Res. 316, 1324–1331 (2010).
7. Sun, Y. et al. Nat. Med. 18, 1359–1368 (2012).8. Straussman, R. et al. Nature 487, 500–504
(2012).9. Wilson, T.R. et al. Nature 487, 505–509 (2012).10. Acharyya, S. et al. Cell 150, 165–178 (2012).11. Nakasone, E.S. et al. Cancer Cell 21, 488–503
(2012).12. McMillin, D.W. et al. Nat. Med. 16, 483–489 (2010).13. Martinez-Outschoorn, U.E. et al. Cancer Biol. Ther. 12,
924–938 (2011).14. Pontiggia, O. et al. Breast Cancer Res. Treat. 133,
Am. J. Pathol. 170, 1546–1560 (2007).16. Johansson, A.C. et al. Mol. Cancer Res.
doi:10.1158/1541-7786.MCR-12-0030 (18 July 2012).
17. Wang, W. et al. Clin. Cancer Res. 15, 6630–6638 (2009).
18. Lindström, L.S. et al. J. Clin. Oncol. 30, 2601–2608 (2012).
HSC maintenance and exhaustion3. Although the relationships between glycolysis, energy homeostasis and HSC function are just beginning to be understood4–7, the contribution of lipid metabolism to HSC maintenance was unknown. In their new work, Ito et al.2 first showed that conditional deletion ex vivo of Ppard (which encodes PPARδ) in mouse bone marrow cells enriched for HSCs and hematopoietic progenitors (KSL (cKit+Sca+Lin−) cells) resulted in enhanced exit of HSCs from quiescence and decreased HSC engrafting capabilities in serial bone
HSCs found in bone marrow, cord blood and growthfactor–mobilized peripheral blood are used to treat and cure patients with a range of malignancies and hematological disorders. However, to use HSCs more efficaciously for treatment, indepth
knowledge is needed of the intracellular controls that regulate HSC selfrenewal and differentiation in response to cytokines and other cells1. In this issue of Nature Medicine, Ito et al.2 describe a new pathway controlling HSC maintenance that encompasses the promyelocyte leukemia (PML) tumor suppressor gene, peroxisome proliferator–activated receptor δ (PPARδ) and FAO, which they link to the regulation of asymmetric and symmetric HSC divisions (Fig. 1).
The same group had previously shown that Pml deletion was associated with loss of
Hal E. Broxmeyer and Charlie Mantel are in the
Department of Microbiology and Immunology,
Indiana University School of Medicine, Indianapolis,
A ROSy future for metabolic regulation of HSC divisionHal E Broxmeyer & Charlie Mantel
Unraveling the intracellular networks that regulate the self-renewal and differentiation of hematopoietic stem cells (HSCs) is crucial to enhancing the efficacy of these therapeutic transplantable cells. A newly discovered pathway links a leukemia tumor suppressor gene with a nutrient sensor to regulate fatty-acid oxidation (FAO) and stem cell division—information with the potential for modulating hematopoiesis for clinical advantage (pages 1350–1358).
