B-cell-derived lymphotoxin promotes castration-resistant prostate cancer
Lymphotoxin's role in prostate cancer progression In the early stages of prostate cancer, cancerous cell growth is dependent on androgens, hence the success of prostatectomy, radiation and androgen-ablating drug therapies. With time, the cancer often develops into an androgen-insensitive, thera...
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| Veröffentlicht in: | Nature (London) 2010-03, Vol.464 (7286), p.302-305 |
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| description | Lymphotoxin's role in prostate cancer progression
In the early stages of prostate cancer, cancerous cell growth is dependent on androgens, hence the success of prostatectomy, radiation and androgen-ablating drug therapies. With time, the cancer often develops into an androgen-insensitive, therapy-resistant form with high mortality rates. Work in mouse models of prostate cancer raises the possibility that androgen-ablating therapies may indirectly promote the development of metastatic secondary tumours. Ammirante
et al
. report that in mice with transgene-induced spontaneous prostate cancer, B-cell infiltration, a component of the natural inflammatory response, activates lymphotoxin release, which stimulates metastasis. In the second model, involving subcutaneous transplantation of an androgen-dependent prostate cancer cell line, it is shown that regression of androgen-deprived primary tumours results in an inflammatory response — and lymphotoxin production. Interfering with the lymphotoxin pathway may therefore offer therapeutic strategies for androgen-independent prostate cancer.
In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer.
Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma
1
. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality
2
. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12–18 months
2
. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice
3
. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth
4
. Inflamm |
| doi_str_mv | 10.1038/nature08782 |
| format | Article |
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In the early stages of prostate cancer, cancerous cell growth is dependent on androgens, hence the success of prostatectomy, radiation and androgen-ablating drug therapies. With time, the cancer often develops into an androgen-insensitive, therapy-resistant form with high mortality rates. Work in mouse models of prostate cancer raises the possibility that androgen-ablating therapies may indirectly promote the development of metastatic secondary tumours. Ammirante
et al
. report that in mice with transgene-induced spontaneous prostate cancer, B-cell infiltration, a component of the natural inflammatory response, activates lymphotoxin release, which stimulates metastasis. In the second model, involving subcutaneous transplantation of an androgen-dependent prostate cancer cell line, it is shown that regression of androgen-deprived primary tumours results in an inflammatory response — and lymphotoxin production. Interfering with the lymphotoxin pathway may therefore offer therapeutic strategies for androgen-independent prostate cancer.
In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer.
Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma
1
. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality
2
. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12–18 months
2
. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice
3
. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth
4
. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer
5
. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK)-β and its target NF-κB have important tumour-promoting functions within malignant cells and inflammatory cells
6
. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment
7
,
8
,
9
, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production
10
. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-α, which stimulates metastasis by an NF-κB-independent, cell autonomous mechanism
11
. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-β activation results in production of cytokines that activate IKK-α and STAT3 in CaP cells to enhance hormone-free survival.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature08782</identifier><identifier>PMID: 20220849</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/250/127/1220 ; 631/250/1619/40 ; 692/699/67/589/466 ; 692/700/565/238 ; Androgens - metabolism ; Animals ; Apoptosis ; B-Lymphocytes - metabolism ; Bone marrow ; Development and progression ; Gene expression ; Health aspects ; Hormones, Sex ; Humanities and Social Sciences ; Humans ; I-kappa B Kinase - genetics ; I-kappa B Kinase - metabolism ; Infiltration ; letter ; Lymphocytes ; Lymphotoxin-alpha - metabolism ; Male ; Metastasis ; Mice ; multidisciplinary ; Orchiectomy ; Physiological aspects ; Prostate - metabolism ; Prostate - pathology ; Prostate cancer ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - physiopathology ; Rodents ; Science ; Science (multidisciplinary) ; Survival Analysis ; Tumors</subject><ispartof>Nature (London), 2010-03, Vol.464 (7286), p.302-305</ispartof><rights>Macmillan Publishers Limited. All rights reserved 2010</rights><rights>COPYRIGHT 2010 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Mar 11, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c642t-a3fd3708e529f63742d5763d4ae78655fb747433fd7c91913ebbe85b06e5c22b3</citedby><cites>FETCH-LOGICAL-c642t-a3fd3708e529f63742d5763d4ae78655fb747433fd7c91913ebbe85b06e5c22b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature08782$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature08782$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20220849$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ammirante, Massimo</creatorcontrib><creatorcontrib>Luo, Jun-Li</creatorcontrib><creatorcontrib>Grivennikov, Sergei</creatorcontrib><creatorcontrib>Nedospasov, Sergei</creatorcontrib><creatorcontrib>Karin, Michael</creatorcontrib><title>B-cell-derived lymphotoxin promotes castration-resistant prostate cancer</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Lymphotoxin's role in prostate cancer progression
In the early stages of prostate cancer, cancerous cell growth is dependent on androgens, hence the success of prostatectomy, radiation and androgen-ablating drug therapies. With time, the cancer often develops into an androgen-insensitive, therapy-resistant form with high mortality rates. Work in mouse models of prostate cancer raises the possibility that androgen-ablating therapies may indirectly promote the development of metastatic secondary tumours. Ammirante
et al
. report that in mice with transgene-induced spontaneous prostate cancer, B-cell infiltration, a component of the natural inflammatory response, activates lymphotoxin release, which stimulates metastasis. In the second model, involving subcutaneous transplantation of an androgen-dependent prostate cancer cell line, it is shown that regression of androgen-deprived primary tumours results in an inflammatory response — and lymphotoxin production. Interfering with the lymphotoxin pathway may therefore offer therapeutic strategies for androgen-independent prostate cancer.
In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer.
Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma
1
. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality
2
. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12–18 months
2
. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice
3
. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth
4
. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer
5
. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK)-β and its target NF-κB have important tumour-promoting functions within malignant cells and inflammatory cells
6
. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment
7
,
8
,
9
, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production
10
. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-α, which stimulates metastasis by an NF-κB-independent, cell autonomous mechanism
11
. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-β activation results in production of cytokines that activate IKK-α and STAT3 in CaP cells to enhance hormone-free survival.</description><subject>631/250/127/1220</subject><subject>631/250/1619/40</subject><subject>692/699/67/589/466</subject><subject>692/700/565/238</subject><subject>Androgens - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>B-Lymphocytes - metabolism</subject><subject>Bone marrow</subject><subject>Development and progression</subject><subject>Gene expression</subject><subject>Health aspects</subject><subject>Hormones, Sex</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>I-kappa B Kinase - genetics</subject><subject>I-kappa B Kinase - metabolism</subject><subject>Infiltration</subject><subject>letter</subject><subject>Lymphocytes</subject><subject>Lymphotoxin-alpha - metabolism</subject><subject>Male</subject><subject>Metastasis</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Orchiectomy</subject><subject>Physiological aspects</subject><subject>Prostate - metabolism</subject><subject>Prostate - pathology</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Prostatic Neoplasms - physiopathology</subject><subject>Rodents</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Survival 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lymphotoxin promotes castration-resistant prostate cancer</title><author>Ammirante, Massimo ; Luo, Jun-Li ; Grivennikov, Sergei ; Nedospasov, Sergei ; Karin, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c642t-a3fd3708e529f63742d5763d4ae78655fb747433fd7c91913ebbe85b06e5c22b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>631/250/127/1220</topic><topic>631/250/1619/40</topic><topic>692/699/67/589/466</topic><topic>692/700/565/238</topic><topic>Androgens - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>B-Lymphocytes - metabolism</topic><topic>Bone marrow</topic><topic>Development and progression</topic><topic>Gene expression</topic><topic>Health aspects</topic><topic>Hormones, Sex</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>I-kappa B Kinase - genetics</topic><topic>I-kappa B Kinase - metabolism</topic><topic>Infiltration</topic><topic>letter</topic><topic>Lymphocytes</topic><topic>Lymphotoxin-alpha - metabolism</topic><topic>Male</topic><topic>Metastasis</topic><topic>Mice</topic><topic>multidisciplinary</topic><topic>Orchiectomy</topic><topic>Physiological aspects</topic><topic>Prostate - metabolism</topic><topic>Prostate - pathology</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Prostatic Neoplasms - physiopathology</topic><topic>Rodents</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Survival Analysis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ammirante, Massimo</creatorcontrib><creatorcontrib>Luo, Jun-Li</creatorcontrib><creatorcontrib>Grivennikov, Sergei</creatorcontrib><creatorcontrib>Nedospasov, Sergei</creatorcontrib><creatorcontrib>Karin, 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(London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2010-03-11</date><risdate>2010</risdate><volume>464</volume><issue>7286</issue><spage>302</spage><epage>305</epage><pages>302-305</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Lymphotoxin's role in prostate cancer progression
In the early stages of prostate cancer, cancerous cell growth is dependent on androgens, hence the success of prostatectomy, radiation and androgen-ablating drug therapies. With time, the cancer often develops into an androgen-insensitive, therapy-resistant form with high mortality rates. Work in mouse models of prostate cancer raises the possibility that androgen-ablating therapies may indirectly promote the development of metastatic secondary tumours. Ammirante
et al
. report that in mice with transgene-induced spontaneous prostate cancer, B-cell infiltration, a component of the natural inflammatory response, activates lymphotoxin release, which stimulates metastasis. In the second model, involving subcutaneous transplantation of an androgen-dependent prostate cancer cell line, it is shown that regression of androgen-deprived primary tumours results in an inflammatory response — and lymphotoxin production. Interfering with the lymphotoxin pathway may therefore offer therapeutic strategies for androgen-independent prostate cancer.
In a mouse model of prostate cancer it is shown that infiltrating B cells promote tumorigenesis by secreting lymphotoxin. Lymphotoxin accelerates the emergence of castration-resistant prostate tumours in this model. Interfering with this pathway may offer therapeutic strategies for androgen-independent prostate cancer.
Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma
1
. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality
2
. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12–18 months
2
. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice
3
. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth
4
. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer
5
. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK)-β and its target NF-κB have important tumour-promoting functions within malignant cells and inflammatory cells
6
. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment
7
,
8
,
9
, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production
10
. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-α, which stimulates metastasis by an NF-κB-independent, cell autonomous mechanism
11
. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-β activation results in production of cytokines that activate IKK-α and STAT3 in CaP cells to enhance hormone-free survival.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>20220849</pmid><doi>10.1038/nature08782</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2010-03, Vol.464 (7286), p.302-305 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2866639 |
| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| subjects | 631/250/127/1220 631/250/1619/40 692/699/67/589/466 692/700/565/238 Androgens - metabolism Animals Apoptosis B-Lymphocytes - metabolism Bone marrow Development and progression Gene expression Health aspects Hormones, Sex Humanities and Social Sciences Humans I-kappa B Kinase - genetics I-kappa B Kinase - metabolism Infiltration letter Lymphocytes Lymphotoxin-alpha - metabolism Male Metastasis Mice multidisciplinary Orchiectomy Physiological aspects Prostate - metabolism Prostate - pathology Prostate cancer Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Prostatic Neoplasms - physiopathology Rodents Science Science (multidisciplinary) Survival Analysis Tumors |
| title | B-cell-derived lymphotoxin promotes castration-resistant prostate cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T00%3A23%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=B-cell-derived%20lymphotoxin%20promotes%20castration-resistant%20prostate%20cancer&rft.jtitle=Nature%20(London)&rft.au=Ammirante,%20Massimo&rft.date=2010-03-11&rft.volume=464&rft.issue=7286&rft.spage=302&rft.epage=305&rft.pages=302-305&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature08782&rft_dat=%3Cgale_pubme%3EA221336108%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=204552531&rft_id=info:pmid/20220849&rft_galeid=A221336108&rfr_iscdi=true |