Focal Adhesion Kinase and Wnt Signaling Regulate Human Ductal Carcinoma In Situ Stem Cell Activity and Response to Radiotherapy

Abstract

Cancer stem cells (CSCs) can avoid or efficiently repair DNA damage from radio and chemotherapy, which suggests they play a role in disease recurrence. Twenty percentage of patients treated with surgery and radiotherapy for ductal carcinoma in situ (DCIS) of the breast recur and our previous data show that high grade DCIS have increased numbers of CSCs. Here, we investigate the role of focal adhesion kinase (FAK) and Wnt pathways in DCIS stem cells and their capacity to survive irradiation. Using DCIS cell lines and patient samples, we demonstrate that CSC-enriched populations are relatively radioresistant and possess high FAK activity. Immunohistochemical studies of active FAK in DCIS tissue show high expression was associated with a shorter median time to recurrence. Treatment with a FAK inhibitor or FAK siRNA in nonadherent and three-dimensional matrigel culture reduced mammosphere formation, and potentiated the effect of 2 Gy irradiation. Moreover, inhibition of FAK in vitro and in vivo decreased selfrenewal capacity, levels of Wnt3a and B-Catenin revealing a novel FAK-Wnt axis regulating DCIS stem cell activity. Overall, these data establish that the FAK-Wnt axis is a promising target to eradicate self-renewal capacity and progression of human breast cancers. STEM CELLS

Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

“…In particular, it has been suggested that a small subpopulation of cells within tumors, called cancer stem cells (CSCs), by virtue of their relative resistance to chemotherapy may contribute to tumor recurrence (5,6). Consistent with these reports, several groups reported enrichment for CSCs when solid cancers were subjected to classical anticancer treatment (7)(8)(9)(10)(11). In accumulation, these studies suggest that significant improvement in patient outcome will require drugs that selectively target CSCs in combination with conventional chemotherapeutic regimens that target rapidly proliferating cells.…”

“…An explanation for this observation is partly provided by existing reports that NACT leads to enrichment of CSCs (7)(8)(9)(10)(11)39). However, this explanation alone is not enough to reason the recurrence of tumors as the CSC subpopulation, being a part of the primary tumor itself, must get removed during surgical resection of the tumor mass.…”

Plasminogen activator inhibitor‐1 as regulator of tumor‐initiating cell properties in head and neck cancers

“…In a study of mouse macrophages, PAI‐1 could induce the phosphorylation of focal adhesion kinase (FAK) to enhance the migration of macrophages . Treatment of FAK inhibitors or knockdown FAK expression by siRNA could reduce the self‐renewal capability and increase the radiosensitivity of ductal carcinoma in situ of breast cancer . The FAK expression in OSCC was significantly correlated with tumor size, neck node metastasis, and local recurrence .…”

Advanced Image Analysis of Stem Cells and Tumor Initiating Cells

“…accurate quantitative assessment of their existence along with related biomarker expression in a tissue context will be essential to the design of therapeutic approaches that can deliver significant improvements in long term patient survival [2][3][4].…”

“…Image analysis in this context can help go beneath the surface of tissue-based experiments, providing quantitative information on TICs that could help inform treatment decisions in a tumorspecific manner. Once target populations are identified, further image analysis studies of TICs can provide quantitative target engagement data, as shown in the case of FAK inhibition in breast cancer TICs [2]. Additionally, CNT helped improve the definition of TICs in renal cell carcinomas, where automated assessments of tumor cells demonstrated underestimation of TICs in RCC and highlighted shortcomings in limited dilution assays frequent used for the experiment identification of TIC populations [16].…”