Abstract
Recent work suggests that the dissemination of tumor cells may occur in parallel with, and even preceed, tumor growth. The mechanism for this early invasion is largely unknown. Here, we find that mammary epithelial cells (MECs) induce neighboring breast carcinoma cells (BCCs) to cross the basement membrane by secreting soluble laminin. Laminin continuously produced by MECs induce long membrane cellular protrusions in BCCs that promote their contractility and invasion into the surrounding matrix. These protrusions depend on microtubule bundles assembled de novo through laminin-integrin β1 signaling. These results describe how non-cancerous MECs can actively participate in the invasive process of BCCs.
Highlights
Local invasion is the first and critical step in cancer metastasis
Across all conditions we examined in this study, we found that invasive breast carcinoma cells (BCCs) were accompanied by a protrusive morphology, indicating that the formation of microtubule-based protrusions is pre-required for MECinduced invasion of BCCs
This stimulation is unidirectional, going from the normal epithelial cells to cancer cells, i.e. this is not a result of a cooptation by cancer cells. This protrusive phenotype is triggered by laminin-integrin interactions at the surface of carcinoma cells, as evidenced by removing laminin from the conditioned medium obtained from mammary epithelial cells (MECs) or by depleting the laminin-receptor β1 integrin in carcinoma cells
Summary
Local invasion is the first and critical step in cancer metastasis. Carcinoma cells must breach the basement membrane barriers in order to invade lymphatic or blood vessels located within the interstitial stroma, which mediates their distant metastasis [1]. Accumulating clinical observations suggest that the formation of long cellular protrusions is critical for cancer invasion [2, 3]. Most cells that fail to form protrusions demonstrate inefficient invasion in gels comprised of basement membrane proteins [10,11,12]. We hypothesize that specific soluble factors may be required to sufficiently stimulate carcinoma cells to form invasive protrusions to overcome the basement membrane barrier
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