Neoadjuvant therapy alters the collagen architecture of pancreatic cancer tissue via Ephrin-A5

Nakajima, Kosei; Ino, Yoshinori; Naito, Chie; Nara, Satoshi; Shimasaki, Mari; Ishimoto, Utako; Iwasaki, Tetsushi; Doi, Noriteru; Esaki, Minoru; Kishi, Yoji; Shimada, Kazuaki; Hiraoka, Nobuyoshi

doi:10.1038/s41416-021-01639-9

Cited by 14 publications

(12 citation statements)

References 43 publications

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“…Our findings are largely in line with a recent gene expression‐ and immunohistochemistry‐based study that reported an altered collagen pattern after neoadjuvant therapy, including depletion of collagen types I, III, IV and V; however, 20 NCT and 5 NCRT patients were analysed together. In vitro analysis indicated that the collagen depletion might contribute to tumor shrinkage 35 . In addition, collagen type I and MMP14 are reported to promote gemcitabine resistance in PDAC and are often found overexpressed in PDAC 36,37 .…”

Section: Resultsmentioning

confidence: 99%

“…In vitro analysis indicated that the collagen depletion might contribute to tumor shrinkage. 35 In addition, collagen type I and MMP14 are reported to promote gemcitabine resistance in PDAC and are often found overexpressed in PDAC. 36,37 In our proteomic comparison, we showed that collagens are enriched in NCRT as compared to NCT.…”

Section: Nct Yields Enrichment Of Ribosomal and Metabolic Proteins As...mentioning

confidence: 99%

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Neoadjuvant chemo‐ or chemo‐radiation‐therapy of pancreatic ductal adenocarcinoma differentially shift ECM composition, complement activation, energy metabolism and ribosomal proteins of the residual tumor mass

Stillger,

Kurowski,

Bronsert

et al. 2024

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, often diagnosed at stages that dis‐qualify for surgical resection. Neoadjuvant therapies offer potential tumor regression and improved resectability. Although features of the tumor biology (e.g., molecular markers) may guide adjuvant therapy, biological alterations after neoadjuvant therapy remain largely unexplored. We performed mass spectrometry to characterize the proteomes of 67 PDAC resection specimens of patients who received either neoadjuvant chemo (NCT) or chemo‐radiation (NCRT) therapy. We employed data‐independent acquisition (DIA), yielding a proteome coverage in excess of 3500 proteins. Moreover, we successfully integrated two publicly available proteome datasets of treatment‐naïve PDAC to unravel proteome alterations in response to neoadjuvant therapy, highlighting the feasibility of this approach. We found highly distinguishable proteome profiles. Treatment‐naïve PDAC was characterized by enrichment of immunoglobulins, complement and extracellular matrix (ECM) proteins. Post‐NCT and post‐NCRT PDAC presented high abundance of ribosomal and metabolic proteins as compared to treatment‐naïve PDAC. Further analyses on patient survival and protein expression identified treatment‐specific prognostic candidates. We present the first proteomic characterization of the residual PDAC mass after NCT and NCRT, and potential protein candidate markers associated with overall survival. We conclude that residual PDAC exhibits fundamentally different proteome profiles as compared to treatment‐naïve PDAC, influenced by the type of neoadjuvant treatment. These findings may impact adjuvant or targeted therapy options.

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Section: Resultsmentioning

confidence: 99%

Section: Nct Yields Enrichment Of Ribosomal and Metabolic Proteins As...mentioning

confidence: 99%

Neoadjuvant chemo‐ or chemo‐radiation‐therapy of pancreatic ductal adenocarcinoma differentially shift ECM composition, complement activation, energy metabolism and ribosomal proteins of the residual tumor mass

Stillger,

Kurowski,

Bronsert

et al. 2024

Intl Journal of Cancer

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“…Another relative limitation might be the lack of pretherapeutic tissue samples to investigate stromal marker changes over the course of neoadjuvant treatment, although our major findings pertain not to differential expression but instead differential association of tissue markers with prognosis between treatment cohorts. Other groups have reported controversial results on stromal markers after NT: Nakajima et al found reduced collagen content for several collagen subtypes but not reduced α-SMA in 25 patients after NT; collagen reduction furthermore correlated with radiographic chemotherapy response [ 29 ]. However, the cohort was not stratified by type of NT and comprised seven different regimens, including S-1, which is currently not part of any treatment algorithms outside of Asia.…”

Section: Discussionmentioning

confidence: 99%

Myofibroblastic CAF Density, Not Activated Stroma Index, Indicates Prognosis after Neoadjuvant Therapy of Pancreatic Carcinoma

Heger

Martens

Schillings

et al. 2022

Cancers

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Neoadjuvant therapy (NT) for advanced PDAC is an emerging concept, affecting both stroma and tumor. The Activated Stroma Index (ASI; ratio of activated cancer-associated fibroblasts (CAF) to collagen deposition) is a prognostic marker in upfront resected pancreatic adenocarcinoma (PDAC). We assessed ASI and its prognostic relevance after NT. Tissue from resection specimens of n = 48 PDAC patients after neoadjuvant chemotherapy with FOLFIRINOX (FOL; n = 31), gemcitabine + nab-paclitaxel (GEM; 7) or combination treatment (COMB; 10) was compared with upfront resected matched controls (RES; 69). Activated CAFs were assessed by immunohistochemistry for α-SMA, and collagen was stained with aniline blue; the stained area was then determined by computational imaging analysis and ASI was calculated. In GEM, ASI was significantly higher and collagen deposition lower than in controls and FOL. The lowest quartile of ASI values had significantly longer overall survival (OS) in RES, whereas in FOL, the highest quartile had the best prognosis. After NT, OS was significantly improved in the α-SMA-high group; in RES, however, survival was independent of α-SMA. Reversed prognostic association of ASI thus points to the differing significance of stromal composition after FOL, while improved prognosis with high CAF abundance suggests a synergistic effect of myofibroblasts with chemotherapy. These divergences impede usability of ASI after NT.

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“…Collagen has been reported to increase tumor tissue stiffness, regulate tumor immunity, and promote metastasis ( 46 ). After neoadjuvant therapy (FOLFIRINOX/AG/gemcitabine/gemcitabine + S1/S1 + irinotecan + oxaliplatin/S1 + radiation(50 Gy)/gemcitabine + S1 + radiation (50 Gy)), the expression of type I, III, IV, and V collagens in pancreatic cancer tissue was decreased ( 47 ). The mechanism of this remodeling may be that these neoadjuvant regimens reduced the expression of ephrin-A5, the upstream regulatory gene of collagen synthesis in CAFs, which leads to significant alterations in the expression level of the collagen gene, thus inducing a reduction in collagen volume in the TME ( 47 ).…”

Section: Effects Of Neoadjuvant Therapy On the Pancreatic Tumor Micro...mentioning

confidence: 99%

“…After neoadjuvant therapy (FOLFIRINOX/AG/gemcitabine/gemcitabine + S1/S1 + irinotecan + oxaliplatin/S1 + radiation(50 Gy)/gemcitabine + S1 + radiation (50 Gy)), the expression of type I, III, IV, and V collagens in pancreatic cancer tissue was decreased ( 47 ). The mechanism of this remodeling may be that these neoadjuvant regimens reduced the expression of ephrin-A5, the upstream regulatory gene of collagen synthesis in CAFs, which leads to significant alterations in the expression level of the collagen gene, thus inducing a reduction in collagen volume in the TME ( 47 ). The remodeling of CAFs and collagens by neoadjuvant chemotherapy/chemoradiotherapy is associated with tumor softening and tumor shrinkage, which may allow the surgical removal of pancreatic cancer, but this softening is often difficult to detect on radiologic imaging.…”

Section: Effects Of Neoadjuvant Therapy On the Pancreatic Tumor Micro...mentioning

confidence: 99%

Neoadjuvant therapy alters the immune microenvironment in pancreatic cancer

Zhang

Lei

et al. 2022

Front. Immunol.

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Pancreatic cancer has an exclusive inhibitory tumor microenvironment characterized by a dense mechanical barrier, profound infiltration of immunosuppressive cells, and a lack of penetration of effector T cells, which constitute an important cause for recurrence and metastasis, resistance to chemotherapy, and insensitivity to immunotherapy. Neoadjuvant therapy has been widely used in clinical practice due to its many benefits, including the ability to improve the R0 resection rate, eliminate tumor cell micrometastases, and identify highly malignant tumors that may not benefit from surgery. In this review, we summarize multiple aspects of the effect of neoadjuvant therapy on the immune microenvironment of pancreatic cancer, discuss possible mechanisms by which these changes occur, and generalize the theoretical basis of neoadjuvant chemoradiotherapy combined with immunotherapy, providing support for the development of more effective combination therapeutic strategies to induce potent immune responses to tumors.

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Neoadjuvant therapy alters the collagen architecture of pancreatic cancer tissue via Ephrin-A5

Cited by 14 publications

References 43 publications

Neoadjuvant chemo‐ or chemo‐radiation‐therapy of pancreatic ductal adenocarcinoma differentially shift ECM composition, complement activation, energy metabolism and ribosomal proteins of the residual tumor mass

Neoadjuvant chemo‐ or chemo‐radiation‐therapy of pancreatic ductal adenocarcinoma differentially shift ECM composition, complement activation, energy metabolism and ribosomal proteins of the residual tumor mass

Myofibroblastic CAF Density, Not Activated Stroma Index, Indicates Prognosis after Neoadjuvant Therapy of Pancreatic Carcinoma

Neoadjuvant therapy alters the immune microenvironment in pancreatic cancer

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