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Mammary Tumorigenesis through LPA Receptor Signaling

2009; Cell Press; Volume: 15; Issue: 6 Linguagem: Inglês

10.1016/j.ccr.2009.05.003

1878-3686

Jos Jonkers, Wouter H. Moolenaar,

Endoplasmic Reticulum Stress and Disease

Lysophosphatidic acid (LPA) is a lipid growth factor that is produced by an extracellular phospholipase, termed autotaxin (ATX), and acts via G protein-coupled receptors. In this issue of Cancer Cell, Liu et al. show that transgenic overexpression of ATX or LPA receptors leads to invasive and metastatic mammary cancer. Lysophosphatidic acid (LPA) is a lipid growth factor that is produced by an extracellular phospholipase, termed autotaxin (ATX), and acts via G protein-coupled receptors. In this issue of Cancer Cell, Liu et al. show that transgenic overexpression of ATX or LPA receptors leads to invasive and metastatic mammary cancer. Lysophosphatidic acid (LPA; mono-acyl-sn-glycero-3-phosphate) (Figure 1) is a bioactive phospholipid that stimulates the proliferation, migration, and survival of many cell types. Its "lyso" prefix notwithstanding, LPA has no membrane-perturbing effects but acts as a high-affinity ligand for specific G protein-coupled receptors. To date, there are six confirmed LPA receptors (termed LPA1–6), which show a broad tissue distribution and have overlapping signaling properties (van Meeteren and Moolenaar, 2007van Meeteren L.A. Moolenaar W.H. Prog. Lipid Res. 2007; 46: 145-160Crossref PubMed Scopus (283) Google Scholar). LPA signaling has been implicated in a great variety of biological processes, ranging from vascular development and neurite remodeling to inflammation and tumor progression. This multitude of activities may seem confusing but is consistent with the ubiquitous expression of LPA receptors and their coupling to a great diversity of G protein-mediated signaling pathways, including those initiated by Ras and Rho GTPases (van Meeteren and Moolenaar, 2007van Meeteren L.A. Moolenaar W.H. Prog. Lipid Res. 2007; 46: 145-160Crossref PubMed Scopus (283) Google Scholar). The three classic LPA receptors, termed LPA1–3, belong to the so-called EDG family of G protein-coupled receptors. The more recently identified LPA receptors, LPA4–6, are related to the purinergic P2Y receptor family but are far distant from the EDG receptors, implying that LPA receptors have evolved from distinct ancestor genes. LPA is produced extracellularly from more complex lysophospholipids, particularly lysophosphatidylcholine (LPC, the most abundant phospholipid in plasma), by a secreted (lyso)phospholipase D named autotaxin (ATX; also known as NPP2, nucleotide pyrophosphatase/phosphodiesterase 2), as illustrated in Figure 1 (van Meeteren and Moolenaar, 2007van Meeteren L.A. Moolenaar W.H. Prog. Lipid Res. 2007; 46: 145-160Crossref PubMed Scopus (283) Google Scholar). ATX was originally identified as an "autocrine motility factor" for human melanoma cells, but its mode of action has remained elusive for a decade until it was discovered that ATX is identical to plasma lysophospholipase D, converting LPC to LPA. ATX is widely expressed, with highest mRNA levels detected in brain, lymph nodes, kidney, and testis; it is found overexpressed in various cancers. Gene targeting studies in mice indicate that ATX (encoded by Enpp2) is essential for vascular development, an unexpected finding given that none of the previous LPA receptor knockouts has hinted at a role for LPA in vasculogenesis (van Meeteren and Moolenaar, 2007van Meeteren L.A. Moolenaar W.H. Prog. Lipid Res. 2007; 46: 145-160Crossref PubMed Scopus (283) Google Scholar). Given its growth factor-like activities, it is not surprising that LPA has long been implicated in cancer. The oncogenic potential of the ATX-LPA receptor axis has become evident from studies in nude mice. In xenografted NIH 3T3 cells, overexpressed ATX cooperates with activated Ras to promote tumor aggressiveness and metastasis (Nam et al., 2000Nam S.W. Clair T. Campo C.K. Lee H.Y. Liotta L.A. Stracke M.L. Oncogene. 2000; 19: 241-247Crossref PubMed Scopus (157) Google Scholar). Overexpression of LPA1 in MDA-MB-231 breast carcinoma cells enhances tumor growth and promotes metastasis to bone (Boucharaba et al., 2004Boucharaba A. Serre C.M. Gres S. Saulnier-Blache J.S. Bordet J.C. Guglielmi J. Clezardin P. Peyruchaud O. J. Clin. Invest. 2004; 114: 1714-1725Crossref PubMed Scopus (348) Google Scholar), whereas overexpression of LPA1, LPA2, and LPA4 (but not LPA3) in embryonic fibroblasts induces cell transformation and tumor formation in conjunction with MYC and TBX2 (Taghavi et al., 2008Taghavi P. Verhoeven E. Jacobs J.J. Lambooij J.P. Stortelers C. Tanger E. Moolenaar W.H. van Lohuizen M. Oncogene. 2008; 27: 6806-6816Crossref PubMed Scopus (36) Google Scholar). Those studies also indicate that distinct oncogenic events must collaborate with ATX-LPA signaling to induce tumor formation. Of the EDG family LPA receptors, LPA2 provides the strongest case for a causal link to cancer. Not only is LPA2 found overexpressed in various common cancers, including ovarian, colon, gastric, and invasive ductal breast carcinoma (Kitayama et al., 2004Kitayama J. Shida D. Sako A. Ishikawa M. Hama K. Aoki J. Arai H. Nagawa H. Breast Cancer Res. 2004; 6: R640-R646Crossref PubMed Scopus (86) Google Scholar), but a recent study by Lin et al., 2009Lin S. Wang D. Iyer S. Ghaleb A.M. Shim H. Yang V.W. Chun J. Yun C.C. Gastroenterology. 2009; 136: 1711-1720Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar demonstrates that LPA2 knockout mice have a marked decrease in tumor incidence and progression of chemically induced colon adenocarcinomas. Reduced colon tumorigenesis in the LPA2-null animals correlated with reduced infiltration by macrophages (Lin et al., 2009Lin S. Wang D. Iyer S. Ghaleb A.M. Shim H. Yang V.W. Chun J. Yun C.C. Gastroenterology. 2009; 136: 1711-1720Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar), one of the predominant stromal cell types that contribute to tumor progression (Joyce and Pollard, 2009Joyce J.A. Pollard J.W. Nat. Rev. Cancer. 2009; 9: 239-252Crossref PubMed Scopus (2484) Google Scholar). Thus, it appears that LPA2 is an important modulator of colon cancer. To determine the importance of LPA2 in other types of cancer, one approach would be to crossbreed LPA2-null mice with genetically engineered mouse tumor models, in which cancer is initiated through Cre-recombinase-mediated activation of oncogenic mutations in specific tissues (Jonkers and Berns, 2002Jonkers J. Berns A. Nat. Rev. Cancer. 2002; 2: 251-265Crossref PubMed Scopus (218) Google Scholar). Now, Liu et al., 2009Liu S. Umezo-Goto M. Murph M. Lu Y. Liu W. Zhang F. Yu S. Stephens C. Cui X. Murrow G. Coombes K. Muller W. Hung M. Perou C. Lee A. Fang X. Mills G.B. Cancer Cell. 2009; 15 (this issue): 539-550Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar have taken a further step forward toward establishing a causal link between ATX-LPA receptor signaling and cancer progression. The authors established transgenic mouse models expressing ATX or each of the three classic LPA receptors (LPA1–3) under the MMTV-LTR promoter. Strikingly, overexpression of either ATX or any of the LPA receptors resulted in mammary carcinomas with variable incidence and metastatic rates. Cancer onset was relatively late, with a latency ranging from 8 to 24 months. Major sites of metastasis were regional lymph nodes and lung, but not bone. Mammary glands from transgenic animals showed a high frequency and early onset of chronic mastitis, indicative of chronic inflammation prior to tumor development. The increased tumor development in the LPA receptor strains suggests that LPA is produced locally at levels sufficient to activate the transgenic LPA receptors. An alternative or additional possibility would be that forced overexpression renders LPA receptors constitutively active in a ligand-independent manner, although there is, as yet, no evidence to support this scenario. Determining local LPA levels in interstitial fluids would be very informative but is technically demanding, if not impossible. Comparative transcriptional profiling revealed that the mammary tumors induced by ATX/LPA receptor overexpression are heterogeneous, scattered throughout various transgenic mammary tumor models, supporting the notion that enforced ATX or LPA receptor expression in mammary glands allows accumulation of secondary transforming mutations leading to late-onset breast cancer development. Such a requirement for additional events is exemplified by the finding that overexpressed LPA receptors can transform fibroblasts only in conjunction with MYC overexpression and reduced p19ARF expression (Taghavi et al., 2008Taghavi P. Verhoeven E. Jacobs J.J. Lambooij J.P. Stortelers C. Tanger E. Moolenaar W.H. van Lohuizen M. Oncogene. 2008; 27: 6806-6816Crossref PubMed Scopus (36) Google Scholar). It is not immediately obvious why overexpression of ATX should lead to the same phenotype as LPA receptor overexpression, as observed by Liu et al., 2009Liu S. Umezo-Goto M. Murph M. Lu Y. Liu W. Zhang F. Yu S. Stephens C. Cui X. Murrow G. Coombes K. Muller W. Hung M. Perou C. Lee A. Fang X. Mills G.B. Cancer Cell. 2009; 15 (this issue): 539-550Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar. In general, increasing ligand concentration is not equivalent to increasing receptor expression levels. One plausible explanation is that ATX secreted by mammary epithelial cells may activate LPA-responsive adjacent cells, such as fibroblasts, leukocytes, and endothelial progenitors, to promote tumorigenesis. In fact, most solid tumors exploit nonmalignant stromal fibroblasts and myeloid cells to increase tumor growth and metastatic potential (Joyce and Pollard, 2009Joyce J.A. Pollard J.W. Nat. Rev. Cancer. 2009; 9: 239-252Crossref PubMed Scopus (2484) Google Scholar). In this respect, it is of note that LPA stimulates normal fibroblasts not only to proliferate and migrate, but also to produce many autocrine/paracrine mediators of tissue remodeling, inflammation, and tumor progression, notably growth factors, chemokines, cytokines, proangiogenic factors, and metalloproteases (Stortelers et al., 2008Stortelers C. Kerkhoven R. Moolenaar W.H. BMC Genomics. 2008; 9: 387Crossref PubMed Scopus (50) Google Scholar). Thus, mammary epithelium-derived ATX is likely to stimulate LPA signaling in nearby fibroblasts, which, in turn, results in the creation of a microenvironment that is permissive for tumor cell growth, invasion, and metastasis. To what extent can the results of Liu et al., 2009Liu S. Umezo-Goto M. Murph M. Lu Y. Liu W. Zhang F. Yu S. Stephens C. Cui X. Murrow G. Coombes K. Muller W. Hung M. Perou C. Lee A. Fang X. Mills G.B. Cancer Cell. 2009; 15 (this issue): 539-550Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar be translated to the human situation? The LPA2 receptor is significantly overexpressed in patients with invasive ductal carcinoma, particularly in postmenopausal women (Kitayama et al., 2004Kitayama J. Shida D. Sako A. Ishikawa M. Hama K. Aoki J. Arai H. Nagawa H. Breast Cancer Res. 2004; 6: R640-R646Crossref PubMed Scopus (86) Google Scholar). Because ATX is also expressed in ductal carcinoma (unpublished data), one can envision a scenario in which ATX and LPA act in an autocrine manner to stimulate the overexpressed LPA2 receptor and thereby promote cancer progression. Although it remains to be seen whether continuous overexpression of either ATX or LPA receptors is required for tumor maintenance, the new findings reinforce the view that ATX and LPA receptors are attractive targets for therapeutic intervention. That ATX is an extracellular enzyme and G protein-coupled receptors, such as those for LPA, are highly "druggable" only adds to their attractiveness. The breast cancer models generated by Liu et al., 2009Liu S. Umezo-Goto M. Murph M. Lu Y. Liu W. Zhang F. Yu S. Stephens C. Cui X. Murrow G. Coombes K. Muller W. Hung M. Perou C. Lee A. Fang X. Mills G.B. Cancer Cell. 2009; 15 (this issue): 539-550Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar and the colon cancer model of Lin et al., 2009Lin S. Wang D. Iyer S. Ghaleb A.M. Shim H. Yang V.W. Chun J. Yun C.C. Gastroenterology. 2009; 136: 1711-1720Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar provide useful tools for developing therapeutics that target the ATX-LPA receptor axis. Expression of Autotaxin and Lysophosphatidic Acid Receptors Increases Mammary Tumorigenesis, Invasion, and MetastasesLiu et al.Cancer CellJune 02, 2009In BriefLysophosphatidic acid (LPA) acts through high-affinity G protein-coupled receptors to mediate a plethora of physiological and pathological activities associated with tumorigenesis. LPA receptors and autotaxin (ATX/LysoPLD), the primary enzyme producing LPA, are aberrantly expressed in multiple cancer lineages. However, the role of ATX and LPA receptors in the initiation and progression of breast cancer has not been evaluated. We demonstrate that expression of ATX or each edg family LPA receptor in mammary epithelium of transgenic mice is sufficient to induce a high frequency of late-onset, estrogen receptor (ER)-positive, invasive, and metastatic mammary cancer. Full-Text PDF Open Archive