Hepatocellular carcinoma remains a lethal malignancy and is an increasingly common cause of cancer death worldwide. Curative-intent surgical resection remains the standard of care for eligible ...patients, yet outcomes remain poor for many patients, with most patients experiencing recurrence in the five years after resection. There is currently significant interest in utilizing locoregional and systemic therapies - in both the neoadjuvant and adjuvant settings - to increase the chance of cure. This review article appraises the existing literature and current clinical trial landscape of neoadjuvant therapies in hepatocellular carcinoma.
Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and ...guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B-an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets-in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the "seeds" of metastasis.
Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require ...tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.
A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence.
Of 103 patients, 84 stage I (9.5%), II (23.8%), III (47.6%), IV (19%) had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (
= 39) or completion of adjuvant therapy (
= 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred positive predictive value (PPV), 100%; HR, 11.28 (
< 0.0001). Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence HR, 1.84 (
= 0.18); PPV = 53.9%.
Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.
.
Cancer growth and metastasis are regulated in part by stromal cells such as fibroblasts and immune cells within the tumor microenvironment. Endothelial cells (ECs) are also ubiquitous within tumors ...because tumors are vascular, and yet, the impact of tumor-resident ECs is less well understood. Through paracrine regulation, ECs modulate a diverse spectrum of pathophysiologic processes in normal and hyperplastic tissues. We hypothesized that ECs offer similar paracrine regulatory control of cancer biology. Indeed, secretions from quiescent ECs muted the proliferative and invasive phenotype of lung and breast cancer cells in vitro and reduced cancer cell protumorigenic and proinflammatory signaling. EC perlecan silencing significantly changed this regulatory relationship, eliminating the ability of ECs to inhibit cancer cell invasiveness via increased interleukin-6 secretion. Moreover, implanting ECs embedded within porous matrices slowed adjacent xenograft tumor growth and prevented architectural degeneration, with a concomitant reduction in proliferative and tumorigenic markers. Finally, lung carcinoma cells pretreated with intact EC-conditioned media, but not media conditioned with perlecan-silenced ECs, exhibited reduced micrometastatic burden after tail vein injection. These findings add to an emerging appreciation of EC-regulatory effects that transcend their structural roles and pave the way for improved characterization and control of EC-cancer cross-talk interactions for diagnosis, prognosis, and treatment of cancer.
Targeted therapies are the mainstay of systemic therapies for patients with advanced, unresectable, or metastatic hepatocellular carcinoma. Several therapeutic targets, such as c-Met, TGF-β, and ...FGFR, have been evaluated in the past, though results from these clinical studies failed to show clinical benefit. However, these remain important targets for the future with novel targeted agents and strategies. The Wnt/β-catenin signaling pathway, c-Myc oncogene, GPC3, PPT1 are exciting novel targets, among others, currently undergoing evaluation. Through this review, we aim to provide an overview of previously evaluated and potentially novel therapeutic targets and explore their continued relevance in ongoing and future studies for HCC.
Although the influence of context‐dependent endothelial cell (EC) regulation of vascular disease and repair is well‐established, the privileged roles ECs play as paracrine regulators of tumor ...progression has only recently become appreciated. We hypothesized that if the same endothelial physiology governs vascular and cancer biology then EC control in cancer should follow endothelial regulation of vascular health. Healthy ECs promote vascular repair and inhibit tumor invasiveness and metastasis. Dysfunctional ECs have the opposite effects in vascular disease, and we now ask if dysfunctionally activated ECs will promote cancer cell inflammatory signaling and aggressive properties. Indeed, while factors released from quiescent ECs induce balanced inflammatory signaling, correlating with decreased proliferation and invasiveness, factors released from dysfunctional ECs robustly activated NF‐κB and STAT3 signaling within cancer cells, correlating with increased in vitro invasiveness and decreased proliferation and survival. Furthermore, matrix‐embedded dysfunctional ECs stimulated intratumoral pro‐inflammatory signaling and spontaneous metastasis, while simultaneously slowing primary tumor growth, when implanted adjacent to Lewis lung carcinoma tumors. These studies may broaden our appreciation of the roles of endothelial function and dysfunction, increase understanding and control of the tumor microenvironment, and facilitate optimization of anti‐angiogenic and vascular‐modifying therapies in cancer and other diseases.
What's new?
It has long been known that the endothelial cells that line blood vessels can influence vascular health, repair, and disease (e.g. plaque formation in atherosclerosis). Researchers have only recently begun to understand, however, the role that endothelial cells play in tumor progression. In this study, the authors found that dysfunctionally activated endothelial cells can stimulate pro‐inflammatory signaling and spontaneous metastasis of lung tumors in mice. Insights into non‐malignant vascular biology may thus potentially guide future work in the vascular biology of cancer.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
