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      Chemotherapy and tumor microenvironment of pancreatic cancer

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          Abstract

          Pancreatic cancer is an extremely dismal malignance. Chemotherapy has been widely applied to treat this intractable tumor. It has exclusive tumor microenvironment (TME), characterized by dense desmoplasia and profound infiltrations of immunosuppressive cells. Interactions between stromal cells and cancer cells play vital roles to affect the biological behaviors of pancreatic cancer. Targeting the stromal components of pancreatic cancer has shown promising results. In addition to the direct toxic effects of chemotherapeutic drugs on cancer cells, they can also remodel the TME, eventually affecting their efficacy. Herein, we reviewed the following four aspects; (1) clinical landmark advances of chemotherapy in pancreatic cancer, since 2000; (2) interactions and mechanisms between stromal cells and pancreatic cancer cells; (3) remodeling effects and mechanisms of chemotherapy on TME; (4) targeting stromal components in pancreatic cancer.

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          The online version of this article (doi:10.1186/s12935-017-0437-3) contains supplementary material, which is available to authorized users.

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          Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.

          David DeNardo, Donal Brennan, Elton Rexhepaj … (2011)
          Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.
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            Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.

            John Neoptolemos, Daniel H Palmer, Paula Ghaneh … (2017)
            The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer.
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              Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.

              Helmut Oettle, Peter Neuhaus, Andreas Hochhaus … (2013)
              The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. isrctn.org Identifier: ISRCTN34802808.
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                Author and article information

                Contributors
                Qiaofei Liu:
                ORCID: http://orcid.org/0000-0001-7148-2850
                qfliu@aliyun.com
                Quan Liao: lqpumc@126.com
                Yupei Zhao: zhao8028@263.net
                Journal
                Journal ID (nlm-ta): Cancer Cell Int
                Journal ID (iso-abbrev): Cancer Cell Int
                Title: Cancer Cell International
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1475-2867
                Publication date (Electronic): 5 July 2017
                Publication date PMC-release: 5 July 2017
                Publication date Collection: 2017
                Volume: 17
                Electronic Location Identifier: 68
                Affiliations
                ISNI 0000 0000 9889 6335, GRID grid.413106.1, Department of General Surgery, , Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, ; 1# Shuai Fu Yuan, Dong Dan District, Beijing, 100730 China
                Author information
                http://orcid.org/0000-0001-7148-2850
                Article
                Publisher ID: 437
                DOI: 10.1186/s12935-017-0437-3
                PMC ID: 5498917
                PubMed ID: 28694739
                SO-VID: 469805a8-5608-4627-a962-83729ac540a9
                Copyright © © The Author(s) 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 29 May 2017
                Date accepted : 20 June 2017
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81502068
                Award ID: 81272573
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81673023
                Award Recipient :
                Funded by: Beijing Natural Science Foundation of China
                Award ID: 7172177
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pancreatic cancer,tumor microenvironment,chemotherapy,myeloid derived suppressor cells,tumor associated macrophages,pancreatic stellate cells,cancer associated fibroblasts
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pancreatic cancer, tumor microenvironment, chemotherapy, myeloid derived suppressor cells, tumor associated macrophages, pancreatic stellate cells, cancer associated fibroblasts

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