Because tumor cell motility is a requirement for metastasis, we hypothesized that lung tissue harbors substances that induce tumor cell migration. MCF‐7 breast carcinoma cells exposed to small airway epithelial cells and conditioned medium exhibited dose‐dependent tumor cell migration. Among the extracellular matrix proteins in the conditioned medium identified by mass spectrometry, laminin 332 (LM332) had the greatest contribution to the migration of MCF‐7 cells. Immunoblotting and immunohistochemistry for LM332‐specific chains identified LM332 in the lung and in pulmonary epithelial cells. Antibodies to either LM332 or its integrin receptor inhibited MCF‐7 motility, and knockdown of LM332 chains also reduced its migration‐inducing activity. Taken together, these findings implicate LM332 as a component of lung tissue that can induce motility in breast carcinoma cells that have been transported to lung during metastasis. Earlier studies on LM332 in tumor progression have examined LM332 expression in tumor cells. This investigation, in comparison, provides evidence that the tumor promoting potential of LM332 may originate in the lung microenvironment rather than in tumor cells alone. Furthermore, this study provides evidence that the motility‐inducing properties of the microenvironment can reside in epithelial cells. The findings raise the possibility that LM332 plays a role in the pulmonary metastases of breast carcinoma and may provide a target for antimetastasis therapy.
In order to determine whether lung tissue secretes a motility factor for breast cancer, minced fresh human pulmonary tissue was co‐cultured with MCF‐7 breast carcinoma cells. Dose‐dependent MCF‐7 migration was observed, consistent with a motility response to a factor secreted by the lung tissue. Pulmonary epithelial cells were isolated and cultured in defined medium. Concentrated conditioned lung culture medium induced motility in the breast carcinoma cell lines MDA‐MB‐231, SKBR3, and BT‐20 using a Boyden chamber assay. For MCF‐7, the motility was dose dependent by a scattering assay, when the concentrate was either in a soluble form or after deposition on tissue culture plastic. The deposited material was analyzed by mass spectrometry, revealing the α3 and β3 chains of the motility factor laminin 332 (LN332). Blocking antibodies to LN332 and to the LN332 receptor for motility, α3β1 integrin, inhibited motility to the same extent as the inhibition of motility that occurred when these antibodies were applied to MCF‐7 cells incubated with purified LN332. Finally, LN332 in normal lung was confirmed by immunohistochemistry. These experiments together showed that pulmonary LN332 induced motility in MCF‐7. These findings provide a mechanism for the migration of metastatic tumor cells from their arrest in the pulmonary vasculature into the surrounding tissue, allowing their establishment as a metastatic colony.
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