Matrix adhesion and remodeling diversifies modes of cancer invasion across spatial scales.

The metastasis of malignant epithelial tumors begins with the egress of transformed cells from the confines of their basement membrane (BM) to their surrounding collagen-rich stroma. Invasion can be morphologically diverse: when breast cancer cells are separately cultured within BM-like matrix, collagen I (Coll I), or a combination of both, they exhibit collective-, dispersed mesenchymal-, and a mixed collective-dispersed (multimodal)- invasion, respectively. In this paper, we asked how distinct these invasive modes are with respect to the cellular and microenvironmental cues that drive them. A rigorous computational exploration of invasion was performed within an experimentally motivated Cellular Potts-based modeling environment. The model comprised of adhesive interactions between cancer cells, BM- and Coll I-like extracellular matrix (ECM), and reaction-diffusion-based remodeling of ECM. The model outputs were parameters cognate to dispersed- and collective- invasion. A clustering analysis of the output distribution curated through a careful examination of subsumed phenotypes suggested at least four distinct invasive states: dispersed, papillary-collective, bulk-collective, and multimodal, in addition to an indolent/non-invasive state. Mapping input values to specific output clusters suggested that each of these invasive states are specified by distinct input signatures of proliferation, adhesion and ECM remodeling. In addition, specific input perturbations allowed transitions between the clusters and revealed the variation in the robustness between the invasive states. Our systems-level approach proffers quantitative insights into how the diversity in ECM microenvironments may steer invasion into diverse phenotypic modes during early dissemination of breast cancer and contributes to tumor heterogeneity.

Testicular Tumors in Undescended Testes in Children Below 5 y of Age.

OBJECTIVE: To evaluate the presentation, treatment and outcome of testicular tumors in undescended testes (UDT) in boys below 5 y of age. METHODS: Case records of boys below 5 y of age, diagnosed to have germ cell tumors (GCT) in the UDT were reviewed. RESULTS: Seven children in the age range of 05-54 mo (mean 26 mo) were included. While five of these 7 (71 %) presented with abdominal mass [one antenatally detected], 2 (29 %) were detected to have a GCT during orchiopexy. In three of these five with abdominal mass, the alpha-fetoprotein (αFP) was markedly elevated. Two of these three with elevated αFP were endodermal sinus tumors while the third was embryonal carcinoma. The 4th patient with an abdominal mass was diagnosed to have an immature teratoma (IMT) while the patient with antenatally diagnosed mass had a mature cystic teratoma (MT). Both the patients with incidentally detected mass during the orchiopexy had mature teratoma (MT). All the seven children are alive and disease free at last follow-up. CONCLUSIONS: Though rare, boys with impalpable undescended testes may develop germ cell tumors early in childhood. These can be managed with chemotherapy and resection and have a good disease free outcome.