RESUMO
Intratumoral heterogeneity (ITH) represents an obstacle for cancer diagnosis and treatment, but little is known about its functional role in cancer progression. The A Desintegrin And Metalloproteinase 23 (ADAM23) gene is epigenetically silenced in different types of tumors, and silencing is often associated with advanced disease and metastasis. Here, we show that invasive breast tumors exhibit significant ADAM23-ITH and that this heterogeneity is critical for tumor growth and metastasis. We demonstrate that while loss of ADAM23 expression enhances invasion, it causes a severe proliferative deficiency and is not itself sufficient to trigger metastasis. Rather, we observed that, in ADAM23-heterotypic environments, ADAM23-negative cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent A23-positive cells through the production of LGI4 (Leucine-rich Glioma Inactivated 4) and nitric oxide (NO). Ablation of LGI4 and NO in A23-negative cells significantly attenuates A23-positive cell proliferation and invasion. Our work denotes a driving role of ADAM23-ITH during disease progression, shifting the malignant phenotype from the cellular to the tissue level. Our findings also provide insights for therapeutic intervention, enforcing the need to ascertain ITH to improve cancer diagnosis and therapy.
Assuntos
Proteínas ADAM/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas da Matriz Extracelular/metabolismo , Óxido Nítrico/metabolismo , Proteínas ADAM/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Epigênese Genética , Proteínas da Matriz Extracelular/genética , Feminino , Inativação Gênica , Humanos , Metástase Neoplásica , Proteínas do Tecido Nervoso , Carga Tumoral , Microambiente TumoralRESUMO
It is known that complete axillary lymph node dissection for breast cancer treatment causes more frequent sensitive and motor alterations in the homolateral shoulder and upper limb than sentinel lymph node (SLN) biopsy. However, it is not clear how often patients treated by SLN biopsy suffer from shoulder mobility (SM) restriction, as well as its severity and duration. This study was done aiming to evaluate SM in 38 patients with early infiltrating breast cancer treated by SLN biopsy in whom shoulder movements were assessed before surgery and repeated at one, two and three months later. Shoulder-arm mobility was evaluated by goniometry considering flexion, abduction, aduction, extension, internal rotation and external rotation. An abnormal result for each movement was defined by restriction greater than ten degrees compared to preoperative findings. Significant abnormal results for flexion and abduction were found in all of the patients at the first month evaluation. At the third month assessment no women showed any kind of SM impairment. The average restriction evolution for each of the parameters is presented. It is concluded that there is frequently a slight and transient SM limitation in patients undergoing SLN biopsy. Early postoperative physiotherapeutical assistance should thus be advisable to relieve and shorten disability symptomatology.
