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An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver.

ABSTRACT: A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule's extent and cellular composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from benign-like NGFR^high stroma at the liver edge to FAP^high stroma towards the tumor. Encapsulation correlates with decreased tumor viability and preoperative chemotherapy. In mice, chemotherapy and tumor cell ablation induce capsule formation. Our results suggest that encapsulation develops where tumor invasion into the liver plates stalls, representing a reparative process rather than tumor-induced desmoplasia. We propose a model of metastases growth, where the efficient tumor colonization of the liver parenchyma and a reparative liver injury reaction are opposing determinants of metastasis aggressiveness.

SUBMITTER: Fernandez Moro C

PROVIDER: S-EPMC10439160 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver.

Fernández Moro Carlos C Geyer Natalie N Harrizi Sara S Hamidi Yousra Y Söderqvist Sara S Kuznyecov Danyil D Tidholm Qvist Evelina E Salmonson Schaad Media M Hermann Laura L Lindberg Amanda A Heuchel Rainer L RL Martín-Bernabé Alfonso A Dhanjal Soniya S Navis Anna C AC Villard Christina C Del Valle Andrea C AC Bozóky Lorand L Sparrelid Ernesto E Dirix Luc L Strell Carina C Östman Arne A Schmierer Bernhard B Vermeulen Peter B PB Engstrand Jennie J Bozóky Béla B Gerling Marco M

Nature communications 20230818 1

A perimetastatic capsule is a strong positive prognostic factor in liver metastases, but its origin remains unclear. Here, we systematically quantify the capsule's extent and cellular composition in 263 patients with colorectal cancer liver metastases to investigate its clinical significance and origin. We show that survival improves proportionally with increasing encapsulation and decreasing tumor-hepatocyte contact. Immunostaining reveals the gradual zonation of the capsule, transitioning from ...[more]

PMID: 37596278

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Project description:BackgroundIn patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy.MethodsAll consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver.ResultsIn total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n = 367), the dHGP was present in 19% (n = 68) and the non-dHGP was present in 81% (n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort (n = 365), more patients were found to express dHGP (n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen.ConclusionsThe current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials.

Project description:Rationale: Dense desmoplastic stroma is a fundamental characteristic of pancreatic ductal adenocarcinoma (PDAC) and comprises up to 80% of the tumor mass. Type I collagen is the major component of the extracellular matrix (ECM), which acts as a barrier to impede the delivery of drugs into the tumor microenvironment. While the strategy to deplete PDAC stroma has failed in clinical trials, normalization of the stroma to allow chemotherapy to kill the tumor cells in the "nest" could be a promising strategy for PDAC therapy. We hypothesize that silencing the poly(rC)-binding protein 2 (αCP2, encoded by the PCBP2 gene) leads to the destabilization and normalization of type I collagen in the PDAC stroma. Methods: We develop a micro-flow mixing method to fabricate a peptide-based core-stabilized PCBP2 siRNA nanocomplex to reverse the accumulation of type I collagen in PDAC tumor stroma. Various in vitro studies were performed to evaluate the silencing activity, cellular uptake, serum stability, and tumor penetration of the PCBP2 siRNA nanocomplex. We also investigated the penetration of small molecules in stroma-rich pancreatic cancer spheroids after the treatment with the PCBP2 siRNA nanocomplex. The anti-tumor activity of the PCBP2 siRNA nanocomplex and its combination with gemcitabine was evaluated in an orthotopic stroma-rich pancreatic cancer mouse model. Results: Silencing the PCBP2 gene using siRNA reverses the accumulation of type I collagen in human pancreatic stellate cells (PSCs) and mouse NIH 3T3 fibroblast cells. The siRNA nanocomplex significantly reduces ECM production and enhances drug penetration through desmoplastic tumor stroma. The combination of gemcitabine with the PCBP2 siRNA nanocomplex markedly suppresses the tumor progression in a desmoplastic PDAC orthotopic mouse model. Conclusion: This approach provides a new therapeutic avenue to improve the antitumor efficacy of PDAC therapies by normalizing tumor stroma using the PCBP2 siRNA nanocomplex.

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An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver.

Publications

An idiosyncratic zonated stroma encapsulates desmoplastic liver metastases and originates from injured liver.

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