Inflammation can play a regulatory role in cancer progression and metastasis. Previously, we have shown that metastatic tumor cells entering the liver trigger a proinflammatory response involving Kupffer cell-mediated release of tumor necrosis factor-␣ and the up-regulation of vascular endothelial cell adhesion receptors, such as E-selectin. Here, we analyzed spatio-temporal aspects of the ensuing tumor-endothelial cell interaction using human colorectal carcinoma CX-1 and murine carcinoma H-59 cells and a combination of immunohistochemistry, confocal microscopy, and threedimensional reconstruction. E-selectin expression was evident mainly on sinusoidal vessels by 6 and 10 hours, The host microenvironment plays an important role in the regulation of tumor progression at the primary site. It can also facilitate tumor dissemination by promoting neovascularization and providing growth-enhancing factors to the metastatic cells at the secondary sites of growth.

Maintenance therapy with olaparib has improved progression-free survival in women with high-grade serous ovarian cancer (HGSOC), particularly those harboring mutations. The objective of this study was to characterize long-term (LT) versus short-term (ST) responders to olaparib. A comparative molecular analysis of Study 19 (NCT00753545), a randomized phase II trial assessing olaparib maintenance after response to platinum-based chemotherapy in HGSOC, was conducted. LT response was defined as response to olaparib/placebo >2 years, ST as <3 months. Molecular analyses included germline status, three-biomarker homologous recombination deficiency (HRD) score, methylation, and mutational profiling. Another olaparib maintenance study (Study 41; NCT01081951) was used as an additional cohort. Thirty-seven LT (32 olaparib) and 61 ST (21 olaparib) patients were identified. Treatment was significantly associated with outcome ( < 0.0001), with more LT patients on olaparib (60.4%) than placebo (11.1%). LT sensitivity to olaparib correlated with complete response to chemotherapy ( < 0.05). In the olaparib LT group, 244 genetic alterations were detected, with , and mutations being most common (90%, 25%, and 35%, respectively). mutations were enriched among the LT responders. methylation was not associated with response duration. High myriad HRD score (>42) and/or mutation was associated with LT response to olaparib. Study 41 confirmed the correlation of LT response with olaparib and mutation. Findings show that LT response to olaparib may be multifactorial and related to homologous recombination repair deficiency, particularly defects. The type of mutation warrants further investigation. .

BackgroundPatients diagnosed with high-grade serous ovarian cancer (HGSOC) who received initial debulking surgery followed by platinum-based chemotherapy can experience highly variable clinical responses. A small percentage of women experience exceptional long-term survival (long term (LT), 10+ years), while others develop primary resistance to therapy and succumb to disease in less than 2 years (short term (ST)). To improve clinical management of HGSOC, there is a need to better characterize clinical and molecular profiles to identify factors that underpin these disparate survival responses.MethodsTo identify clinical and tumor molecular biomarkers associated with exceptional clinical response or resistance, we conducted an integrated clinical, exome, and transcriptome analysis of 41 primary tumors from LT (n = 20) and ST (n = 21) HGSOC patients.ResultsYounger age at diagnosis, no residual disease post debulking surgery and low CA125 levels following surgery and chemotherapy were clinical characteristics of LT. Tumors from LT survivors had increased somatic mutation burden (median 1.62 vs. 1.22 non-synonymous mutations/Mbp), frequent BRCA1/2 biallelic inactivation through mutation and loss of heterozygosity, and enrichment of activated CD4+, CD8+ T cells, and effector memory CD4+ T cells. Characteristics of ST survival included focal copy number gain of CCNE1, lack of BRCA mutation signature, low homologous recombination deficiency scores, and the presence of ESR1-CCDC170 gene fusion.ConclusionsOur findings suggest that exceptional long- or short-term survival is determined by a concert of clinical, molecular, and microenvironment factors.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0590-x) contains supplementary material, which is available to authorized users.