The role of alpha 6 integrin in prostate cancer migration and bone pain in a novel xenograft model

Tamara E. King, Sangita C. Pawar, Lisa Majuta, Isis C Sroka, Danyel Wynn, Manolis C. Demetriou, Raymond B Nagle, Frank Porreca, Anne E Cress

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Of the estimated 565,650 people in the U.S. who will die of cancer in 2008, almost all will have metastasis. Breast, prostate, kidney, thyroid and lung cancers metastasize to the bone. Tumor cells reside within the bone using integrin type cell adhesion receptors and elicit incapacitating bone pain and fractures. In particular, metastatic human prostate tumors express and cleave the integrin A6, a receptor for extracellular matrix components of the bone, i.e., laminin 332 and laminin 511. More than 50% of all prostate cancer patients develop severe bone pain during their remaining lifetime. One major goal is to prevent or delay cancer induced bone pain. We used a novel xenograft mouse model to directly determine if bone pain could be prevented by blocking the known cleavage of the A6 integrin adhesion receptor. Human tumor cells expressing either the wild type or mutated A6 integrin were placed within the living bone matrix and 21 days later, integrin expression was confirmed by RT-PCR, radiographs were collected and behavioral measurements of spontaneous and evoked pain performed. All animals independent of integrin status had indistinguishable tumor burden and developed bone loss 21 days after surgery. A comparison of animals containing the wild type or mutated integrin revealed that tumor cells expressing the mutated integrin resulted in a dramatic decrease in bone loss, unicortical or bicortical fractures and a decrease in the ability of tumor cells to reach the epiphyseal plate of the bone. Further, tumor cells within the bone expressing the integrin mutation prevented cancer induced spontaneous flinching, tactile allodynia, and movement evoked pain. Preventing A6 integrin cleavage on the prostate tumor cell surface decreased the migration of tumor cells within the bone and the onset and degree of bone pain and fractures. These results suggest that strategies for blocking the cleavage of the adhesion receptors on the tumor cell surface can significantly prevent cancer induced bone pain and slow disease progression within the bone. Since integrin cleavage is mediated by Urokinase-type Plasminogen Activator (uPA), further work is warranted to test the efficacy of uPA inhibitors for prevention or delay of cancer induced bone pain.

Original languageEnglish (US)
Article numbere3535
JournalPLoS One
Volume3
Issue number10
DOIs
StatePublished - Oct 28 2008

Fingerprint

Integrin alpha6
Bone Neoplasms
integrins
prostatic neoplasms
Heterografts
Integrins
pain
Prostatic Neoplasms
Bone
bones
Bone and Bones
Pain
Tumors
Neoplasms
Cells
neoplasms
Bone Fractures
Urokinase-Type Plasminogen Activator
u-plasminogen activator
Prostate

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The role of alpha 6 integrin in prostate cancer migration and bone pain in a novel xenograft model. / King, Tamara E.; Pawar, Sangita C.; Majuta, Lisa; Sroka, Isis C; Wynn, Danyel; Demetriou, Manolis C.; Nagle, Raymond B; Porreca, Frank; Cress, Anne E.

In: PLoS One, Vol. 3, No. 10, e3535, 28.10.2008.

Research output: Contribution to journalArticle

King, Tamara E. ; Pawar, Sangita C. ; Majuta, Lisa ; Sroka, Isis C ; Wynn, Danyel ; Demetriou, Manolis C. ; Nagle, Raymond B ; Porreca, Frank ; Cress, Anne E. / The role of alpha 6 integrin in prostate cancer migration and bone pain in a novel xenograft model. In: PLoS One. 2008 ; Vol. 3, No. 10.
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