Periostin: a Bridge Between Cancer Stem Cells and Their Metastatic Niche

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Periostin: A Bridge between Cancer Stem Cells and Their Metastatic Niche

Zhe Wang1,2 and Gaoliang Ouyang1,2,* 1State Key Laboratory of Cellular Stress Biology 2Laboratory of Stem Cells and Tumor Metastasis School of Life Sciences, Xiamen University, Xiamen 361005, China *Correspondence: [email protected] DOI 10.1016/j.stem.2012.01.002

Only a minority of cancer cells have the potential to initiate metastatic growth, but the factors that limit metastatic colonization remain mostly unknown. Malanchi et al. (2012) recently demonstrated that stromal periostin is crucial for metastatic colonization by regulating the interactions between breast cancer stem cells and their metastatic niche.

Tumor metastasis is the most common PyMT mouse breast cancer model, which as a key regulatory factor for lung cause of cancer-associated mortality. To has many characteristics similar to human metastasis of breast tumors. Interestingly, give rise to the outgrowth of metastatic luminal breast cancer and spontaneously POSTN expression is induced in the tumors in a new organ microenvironment, metastasizes to the lungs, Malanchi et al. lung stroma by infiltrating cancer cells. cancer cells have to overcome various (2012) found that only the CD90+CD24+ POSTN expression was increased in iso- types of stresses and several rate-limiting CSC population from primary tumors or lated primary lung fibroblasts treated steps (Bao et al., 2004). Most dissemi- pulmonary metastases was able to pro- with TGF-b3 or TGF-b2 or cocultured nated cancer cells are destroyed during duce lung metastases and initiate sec- with tumor cells. Using a dominant-nega- metastasis formation and only a small ondary metastases. This result, together tive TGFbR2DTM, the authors found that subset of cancer cells are able to sur- with those from previous studies, sup- blocking the action of TGF-b3 in tumor vive and colonize in a new environment. ports the idea that only the CSC subpopu- cells abrogates stromal POSTN expres- Specialized tumor microenvironments lation is able to cause tumor metastasis sion and metastasis formation in lungs. called metastatic niches are thought to and that selective expansion of CSCs is Taken together, these results indicate be responsible for nurturing disseminated responsible for initiating metastasis. that infiltrating tumor cells can educate cancer cells from micrometastases to full Because the metastasis frequency is stromal cells by secreting factors such as macrometastases. Recent studies have much lower than the number of injected TGF-b3, which induces host stromal ex- shown that there may be a direct link CSCs, Malanchi et al. reasoned that spe- pression of POSTN to create a metastatic between cancer stem cells (CSCs) and cialized elements from the foreign micro- niche to support metastasis formation. their metastatic niches. Identifying the environment might govern metastatic Investigating the underlying mecha- limiting factors that regulate the pro- colonization by affecting the maintenance nisms of POSTN-induced metastasis, perties of CSCs and their colonization and expansion of CSCs in metastatic Malanchi et al. (2012) observed that of metastatic niches is therefore impor- sites. To explore the limiting factors POSTN-deficient tumor cells fail to form tant for developing strategies to treat that determine metastatic success, the tumorspheres, but this phenotype can patients with metastatic tumors. In a authors analyzed potential niches in be rescued by adding POSTN protein to recent issue of Nature, Huelsken and mammary gland, bone, skin, and intestine primary cultures. Furthermore, CSCs fail colleagues (Malanchi et al., 2012) provide and identified periostin (Postn)asa to initiate colony formation when cocul- new insight into how signals from the stromal factor of normal stem cell niches. tured with stromal cells isolated from metastatic niche affect CSC self-renewal They demonstrated that POSTN is se- PostnÀ/À lungs, but do form colonies and metastatic colonization. creted by stromal aSMA+VIM+ fibroblasts with wild-type cells. CD90+ CSCs have CSCs are a subpopulation of tumor in the lungs of metastasis-positive ani- a tendency to preferentially localize adja- cells that can drive tumorigenesis via their mals, but not by tumor cells. Furthermore, cent to stromal niches in lung metastases, abilities to self-renew and differentiate, the authors found that while POSTN- whereas the frequency of CD90+CD24+ whereas their counterpart non-CSCs are knockout MMTV-PyMT mice show no dif- CSCs in the rare pulmonary metastases not tumorigenic and are thought to not ferences in primary breast tumor volume in POSTN-deficient mice is reduced. contribute substantially to tumor metas- and morphology compared with wild- Thus, stromal POSTN plays a key role in tasis. Recently, distinct types of CSCs type mice, they have a significantly regulating CSC maintenance and expan- have been shown to determine tumor decreased pulmonary metastasis poten- sion during metastatic colonization. To growth and metastatic activity in human tial, and the metastatic efficiency of investigate how POSTN promotes stem pancreatic cancer (Hermann et al., 2007) POSTN-deficient tumor cells can be re- cell maintenance and metastasis forma- and colorectal/colon cancer (Dieter et al., scued in wild-type recipients. These tion, Malanchi et al. (2012) analyzed the 2011; Pang et al., 2010). Using the MMTV- data suggest that stromal POSTN acts interactome of POSTN and found that

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of the role of POSTN in tumor metastasis in all of these locations. The study from Malanchi et al. (2012) reinforces the notion that there may be functional similarities between matricellular proteins in regulating CSC stemness and metastatic niches. Osteopontin (OPN), tenascin C, and other matricellular proteins also promote tumor metastasis and modulate the maintenance and expansion of normal or cancer stem cells and metastatic niches (McAllister et al., 2008; Oskarsson et al., 2011; Ouyang et al., 2010). Whether and how these matricellular proteins regulate stemness of CSCs as metastatic niche components deserves a systemic evaluation.

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Coutu, D.L., Wu, J.H., Monette, A., Rivard, G.E., Figure 1. Periostin Mediates the Crosstalk between Cancer Stem Cells and Their Niche Blostein, M.D., and Galipeau, J. (2008). J. Biol. Periostin (POSTN) plays an essential role in the crosstalk between cancer stem cells (CSCs) and their niche Chem. 283, 17991–18001. to permit metastatic colonization. (A) Tumor metastasis is initially triggered by cancer stem-like cells. (B and C) The premetastatic niche created by bone-marrow-derived cells is critical for tumor metastasis Dieter, S.M., Ball, C.R., Hoffmann, C.M., Nowrouzi, because it enhances the adhesion of infiltrating tumor cells. (D) Tumor-cell-secreted TGF-b3 educates the A., Herbst, F., Zavidij, O., Abel, U., Arens, A., Wei- 9 lung stroma to create a CSC-supportive niche by inducing the expression of stromal POSTN. POSTN chert, W., Brand, K., et al. (2011). Cell Stem Cell , 357–365. recruits Wnt ligands, thereby augmenting Wnt signaling in CSCs, which promotes CSC self-renewal and metastatic formation. (E) POSTN promotes tumor metastatic growth by promoting both cell survival Hermann, P.C., Huber, S.L., Herrler, T., Aicher, A., and angiogenesis. However, whether POSTN is involved in the formation of the premetastatic and Ellwart, J.W., Guba, M., Bruns, C.J., and Hee- perivascular niches, and thereby in the regulation of CSC maintenance and tumor metastasis, has not schen, C. (2007). Cell Stem Cell 1, 313–323. been characterized (C and F). Kaplan, R.N., Riba, R.D., Zacharoulis, S., Bramley, A.H., Vincent, L., Costa, C., MacDonald, D.D., Jin, D.K., Shido, K., Kerns, S.A., et al. (2005). Nature POSTN increases Wnt signaling by in- role in establishing metastases in the liver 438, 820–827. teracting with Wnt ligands, Wnt1 and microenvironment. These findings are Wnt3A. Interestingly, POSTN-deficient consistent with the conclusion of Malan- Malanchi, I., Santamaria-Martinez, A., Susanto, E., Peng, H., Lehr, H.A., Delaloye, J.F., and Huelsken, mice successfully form pulmonary metas- chi et al. (2012) that POSTN is a critical J. (2012). Nature 481, 85–89. tasis under orthotopical MMTV-Wnt1 limiting factor during metastatic coloni- McAllister, S.S., Gifford, A.M., Greiner, A.L., tumor cell transplantation. These results zation. POSTN can also be secreted Kelleher, S.P., Saelzler, M.P., Ince, T.A., Reinhardt, suggest that stromal POSTN bridges the by bone-marrow-derived mesenchymal F., Harris, L.N., Hylander, B.L., Repasky, E.A., and gap between the metastatic niche and stromal cells and their derived cells Weinberg, R.A. (2008). Cell 133, 994–1005. CSCs to create a CSC-supportive niche (Coutu et al., 2008), and Kaplan et al. Oskarsson, T., Acharyya, S., Zhang, X.H., Vanhar- and promotes metastatic colonization (2005) highlighted that the premetastatic anta, S., Tavazoie, S.F., Morris, P.G., Downey, R.J., Manova-Todorova, K., Brogi, E., and Mas- by augmenting Wnt signaling pathway niche created by bone-marrow-derived sague´ , J. (2011). Nat. Med. 17, 867–874. (Figure 1). cells in secondary sites before the arrival Interestingly, Bao et al. (2004) showed of tumor cells can be a critical microenvi- Ouyang, G., Wang, Z., Fang, X., Liu, J., and Yang, C.J. (2010). Cell. Mol. Life Sci. 67, 2605–2618. previously that overexpression of POSTN ronment for facilitating tumor metastasis, in human colon cancer cells can enhance suggesting another potential site for Pang, R., Law, W.L., Chu, A.C., Poon, J.T., Lam, C.S., Chow, A.K., Ng, L., Cheung, L.W., Lan, the number and size of metastases in the POSTN involvement. Further investigation X.R., Lan, H.Y., et al. (2010). Cell Stem Cell 6, liver, indicating that POSTN plays a critical will no doubt increase our understanding 603–615.

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