The effect of the low stromal ratio induced by neoadjuvant chemotherapy on recurrence patterns in borderline resectable pancreatic ductal adenocarcinoma

The optimal regimens of neoadjuvant chemotherapy (NAC) and its biological and physiological modification of the tumor microenvironment (TME) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR PDAC) remain unknown. A deeper understanding of the complex stromal biology of the TME will identify new avenues to establish treatment strategies for PDAC patients. Herein, we sought to clarify whether stromal remodeling by NAC affects recurrence patterns and prognosis in BR PDAC patients. We retrospectively analyzed data from 104 BR PDAC patients who underwent pancreatectomy with or without NAC (upfront surgery [UpS], n = 44; gemcitabine + nab-paclitaxel [GnP], n = 28; and gemcitabine + S-1 [GS], n = 32) to assess the correlations of treatment with early recurrence, the stromal ratio, and Ki-67 levels. Eighty-six patients experienced recurrence, and those with liver metastasis had significantly shorter recurrence-free survival than those with other recurrence patterns. The frequency of liver metastasis was significantly higher in patients with a low stromal ratio than in those with a high stromal ratio in the NAC group but not in the UpS group. Patients in the GnP group had significantly higher Ki-67 than those in the GS and UpS groups. A low stromal ratio was positively correlated with high Ki-67 in the NAC group but not in the UpS group. The low stromal ratio induced by NAC promoted early liver metastasis in patients with BR PDAC. Our findings provide new insights into the complexity of stromal biology, leading to consideration of the optimal NAC regimen.

Detection of melanoma, breast cancer and head and neck squamous cell cancer sentinel lymph nodes by Tc-99m Tilmanocept (Lymphoseek®)

Technetium-99m-labeled Tilmanocept or Lymphoseek® (Cardinal Health, Dublin, Ohio) is a soluble, synthetic molecule with a small diameter (7 nm), which is comprised of technetium-99m chelated to a dextran backbone containing multiple units of mannose ligands with a high affinity for CD206, a receptor located on the surface of macrophages and dendritic cells that are found in high concentration in lymph nodes. It enables quick transit from the injection site and rapid lymph node accumulation. The binding of mannose ligand and CD206 results in the internalization of the ligand and receptor into the cell. Once the Technetium-99m-labeled Tilmanocept (Lymphoseek®) reaches the lymph node, it is readily internalized by the macrophages and dendritic cells within the draining lymph nodes. Technetium-99m-labeled Tilmanocept (Lymphoseek®) has been extensively studied as a radioisotope for detection of sentinel lymph nodes in melanoma, breast cancer and head and neck squamous cell carcinoma in clinical trials. Based on its safety and ability to detect sentinel lymph nodes satisfactorily, it has been approved by the FDA to use as a radioisotope for preoperative lymphoscintigraphy for identification of sentinel lymph nodes in these types of cancer. Further, the FDA has expanded approval of Technetium-99m-labeled for sentinel lymph node mapping of all solid tumors as well as in pediatric patients.

Defining the landscape of metabolic dysregulations in cancer metastasis

Metastasis is the primary cause of cancer related deaths due to the limited number of efficient druggable targets. Signatures of dysregulated cancer metabolism could serve as a roadmap for the determination of new treatment strategies. However, the metabolic signatures of metastatic cells remain vastly elusive. Our aim was to determine metabolic dysregulations associated with high metastatic potential in breast cancer cell lines. We have selected 5 triple negative breast cancer (TNBC) cell lines including three with high metastatic potential (HMP) (MDA-MB-231, MDA-MB-436, MDA-MB-468) and two with low metastatic potential (LMP) (BT549, HCC1143). The normal epithelial breast cell line (hTERT-HME1) was also investigated. The untargeted metabolic profiling of cells and growth media was conducted and total of 479 metabolites were quantified. First we characterized metabolic features differentiating TNBC cell lines from normal cells as well as identified cell line specific metabolic fingerprints. Next, we determined 92 metabolites in cells and 22 in growth medium that display significant differences between LMP and HMP. The HMP cell lines had elevated level of molecules involved in glycolysis, TCA cycle and lipid metabolism. We identified metabolic advantages of cell lines with HMP beyond enhanced glycolysis by pinpointing the role of branched chain amino acids (BCAA) catabolism as well as molecules supporting coagulation and platelet activation as important contributors to the metastatic cascade. The landscape of metabolic dysregulations, characterized in our study, could serve as a roadmap for the identification of treatment strategies targeting cancer cells with enhanced metastatic potential.

Molecular and cellular mechanisms controlling integrin-mediated cell adhesion and tumor progression in ovarian cancer metastasis: a review

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in the developed world. EOC metastasis is unique since malignant cells detach directly from the primary tumor site into the abdominal fluid and form multicellular aggregates, called spheroids, that possess enhanced survival mechanisms while in suspension. As such, altered cell adhesion properties are paramount to EOC metastasis with cell detachment from the primary tumor, dissemination as spheroids, and reattachment to peritoneal surfaces for secondary tumor formation. The ability for EOC cells to establish and maintain cell–cell contacts in spheroids is critical for cell survival in suspension. Integrins are a family of cell adhesion receptors that play a crucial role in cell–cell and cell-extracellular matrix interactions. These glycoprotein receptors regulate diverse functions in tumor cells and are implicated in multiple steps of cancer progression. Altered integrin expression is detected in numerous carcinomas, where they play a role in cell migration, invasion, and anchorage-independent survival. Like that observed for other carcinomas, epithelial-mesenchymal transition (EMT) occurs during metastasis and integrins can function in this process as well. Herein, we provide a review of the evidence for integrin-mediated cell adhesion mechanisms impacting steps of EOC metastasis. Taken together, targeting integrin function may represent a potential therapeutic strategy to inhibit progression of advanced EOC.

PD-L1 blockade exhibits anti-tumor effect on brain metastasis by activating CD8+ T cells in hematogenous metastasis model with lymphocyte infusion

Brain metastases are common complication in cancer patients. Immune checkpoint inhibitors show therapeutic benefits also in patients with central nervous system (CNS) metastases. However, their antitumor effects on metastatic tumors and their underlying mechanisms are still poorly understood. In this study we investigated the antitumor effect of anti-programmed death-ligand 1 (PD-L1) antibody on metastatic brain tumors and evaluated immune responses during treatment. We employed a hematogenous brain metastasis xenograft model using immunodeficient mice with murine lymphocyte infusions. A human non-small-cell lung cancer (NSCLC) cell line stably expressing NanoLuc® reporter (Nluc-H1915) was inoculated from the internal carotid artery of SCID mice. After metastases were established (24 days after inoculation), splenocytes prepared from H1915-immunized BALB/c mice were injected intravenously and mouse IgG or anti-PD-L1 antibody treatment was started (day 1). Evaluated by Nluc activity, tumor volume in the brain on day 14 was significantly lower in anti-PD-L1-treated mice than in mouse IgG-treated mice. Furthermore CD8+ cells were primarily infiltrated intratumorally and peritumorally and anti-PD-L1 treatment induced a significantly higher proportion of Granzyme B (GzmB)+ cells among CD8+ T cells. The antitumor effect of anti-PD-L1 antibody on brain metastasis is thought to be achieved by the enhanced activation of infiltrated CD8+ T cells into metastatic brain tumor. These results suggest that anti-PD-L1 antibody-containing regimens may be promising treatment options for cancer patients with brain metastases.