Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs

Abstract

We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell–derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat–containing G protein– coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell– derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.

Prognostic Value of Immunohistochemical Expressions of the Stem Cell Biomarker "LGR5" and the Proliferation Biomarker "TPX2" in Colorectal Carcinoma

“…Our results are consistent with previous studies proving that overexpression of LGR5 was associated with poor prognosis in CRC [26][27][28][29] . The current results also are consistent with studies done in other organs stating that LGR5 overexpression is associated with poor prognosis and metastasis-initiating potentials in breast cancer, glioblastoma, lung cancer and esophageal adenocarcinoma [30][31][32][33] .…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Several recent studies implicated fibroblasts in facilitating formation of the metastatic niche: O'Connell et al reported that resident FSP-1 + fibroblasts express VEGF-A and tenascin-C that correlated with increased metastasis in a mouse model of transplantable mammary carcinoma -depletion of fibroblasts or genetic ablation of VEGF-A and tenascin-C resulted in decreased metastatic capacity [102]. These results are supported by the findings of two other groups, demonstrating that expression of the ECM proteins tenascin-C and periostin by stromal fibroblasts in the lungs supports the formation of a metastatic niche that facilitates metastatic colonization of mammary tumour cells, by enhancing WNT signalling [103][104][105]. Expression of periostin by pancreatic stellate cells was also suggested to be in correlation with aggressive behaviour and worse prognosis in pancreatic cancer [106].…”

ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

“…49 papillomas displayed weak tenascin C levels, despite ROCK er -associated NF-κβ expression, With time and/or p53 loss, increased tenascin C expression appeared in the ECM of both wdSCC and surrounding connective tissue, with intense staining appearing as wdSCCs progressed to SCC. [27][28][29][48][49][50] The necessity of continued ROCK er activities for tenascin C expression was shown by cessation experiments and again as endogenous ROCK2/p-Mypt1 appeared, intense tenascin C returned in both tumour and connective tissue ECM to facilitate progression. 28,29 However, following cessation tenascin C repeatedly persisted in connective tissue matrix, but not that of wdSCC tissue; suggesting that once laid down to facilitate conversion, increased tissue rigidity remained.…”

“…28,29 Tenascin C expression reflects tumour aggression and metastatic potential 27,[48][49][50] and also associated with deregulated NF-κβ signalling 48 and NF-κβ roles in inflammation. 49 papillomas displayed weak tenascin C levels, despite ROCK er -associated NF-κβ expression, With time and/or p53 loss, increased tenascin C expression appeared in the ECM of both wdSCC and surrounding connective tissue, with intense staining appearing as wdSCCs progressed to SCC.…”