Review
Reflections on depletion of tumor stroma in pancreatic cancer☆

https://doi.org/10.1016/j.bbcan.2019.01.007Get rights and content

Abstract

Pancreatic cancer characteristically has an extremely dense stroma, which facilitates chemoresistance by creating physical and biological barriers to therapeutic agents. Thus, stroma-depleting agents may enhance the delivery and efficacy of chemotherapy drugs. However, stroma-targeting therapy for pancreatic cancer is a double-edged sword, as the stroma can also inhibit tumor metastasis and malignancy. In-depth understanding of the critical role of the stroma in cancer metastasis may improve therapeutic approaches by allowing them to harness specific features of the stroma to treat pancreatic cancer.

Introduction

Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide, with a 5-year survival rate of <8% [1]. Surgical resection is the only potentially curative therapy for this highly lethal malignancy [2]. However, only 15–20% of pancreatic cancer patients are considered surgery candidates at the time of diagnosis [3]. Comprehensive chemotherapy-based treatment is the primary strategy for the remaining >80% of patients with unresectable disease. Despite significant progress in the development of new chemotherapy regimens [[4], [5], [6], [7], [8]] over the past 20 years, the overall chemotherapeutic efficacy against pancreatic cancer remains low. Therefore, investigation of novel strategies is extremely important for improving pancreatic cancer outcomes. Certain molecular therapies, such as anti-angiogenic agents and epidermal growth factor receptor antagonists, have shown little to no benefit in patients with pancreatic cancer [[9], [10], [11]]. Specific biological mechanisms likely hinder the effectiveness of these therapies.

The highly heterogeneous pancreatic cancers are generally characterized by the presence of a dense stroma, with extensive fibroblasts proliferation and extracellular matrix (ECM) deposition [12]. The stroma can constitute in excess of 50% of the tumor volume, comprising cancer-associated fibroblasts (CAFs), blood vessels, hyaluronan, collagen fibers, infiltrating immune and inflammatory cells, nerve fibers, and adipocytes [12,13]. The de-differentiated tumor cells distributed throughout the stromal components with the immature adenoid structure, when compared with the mature pancreas cell types [12,14]. Within this environment, the intratumoral microvessels are highly compressed, limiting the uptake of chemotherapy agents. These properties create a physical and biochemical barrier that, when coupled with the complex tumor microenvironment and the biological resistance of pancreatic cancer cells to chemotherapy [15,16], results in poor response to most treatment options. Therefore, strategies to eliminate or remodel this physical and biochemical barrier could substantially improve chemotherapy delivery and efficacy.

Section snippets

Overview of stromal biology in pancreatic cancer

Stromal components modulate pancreatic cancer progression [12,17]. CAFs, among the most important constituents of the stroma, play a central role in malignant tumor behavior. They contribute to the establishment of an immunosuppressive tumor microenvironment, the secretion of cytokines that promote tumor growth, metastasis, and chemoresistance, and the induction of systemic effects, such as cachexia and acidosis [[18], [19], [20], [21]]. Collagen fibers, another important stromal component,

Investigations of stroma depletion in pancreatic cancer

Considering the role of the stroma in pancreatic cancer, the underlying pathways represents a target for restraining the malignant behavior. Six major mechanisms drive the generation of desmoplastic stroma: ECM remodeling by secreted protein acidic and rich in cysteine (SPARC) [30], tumor stroma depletion by CD40-activated tumor-associated macrophages [31], microvascular wall collapse derived from tumor endothelial cell damage by gamma-secretase activation in the Notch signaling pathway [32,33

Clinical exploration of stroma-depleting agents

Preclinical studies have highlighted the prospect of utilizing stroma-targeting treatments (Fig. 1), paving the road for several clinical trials examining the use of stroma-depleting agents in pancreatic cancer (Table 1). However, most of these agents did not successfully translate into clinical use. Although the SPARC-targeting chemotherapy drug nab-paclitaxel successfully achieved clinical translation [6,44], later studies demonstrated that its efficacy does not depend on SPARC expression

Causes and prevention of negative effects of stromal depletion

Most mechanistic studies have concluded that the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) plays an essential role in maintaining the malignant biological behavior of the tumor cells [12,25,38]. However, combinations of stromal depletion strategies and systemic chemotherapy have not benefited patients in clinical studies (Table 1) [[49], [50], [51], [52],54], indicating that PDAC stroma likely possess protective biological features. Ozdemir et al. [55], Rhim et al. [56],

Discussion, reflection, and perspective

Clinical studies have not demonstrated that stromal depletion can lead to acceleration of tumor progression and metastasis. However, preclinical studies linking the underlying mechanisms with metastasis (Fig. 1) warn against the implementation of such therapeutic approaches. Notably, different stromal depletion treatment strategies may have mechanism-specific negative outcomes, requiring distinct clinical approaches. Even in the same patient, inherent heterogeneity of the stromal

Financial support

This work was supported by grants from the National Science Foundation for Distinguished Young Scholars of China (81625016), the National Natural Science Foundation of China (81872366, 81472670, 81871941, 81802380, and 81802675), the Outstanding Academic Leader Program of the Technological Innovation Action Plan of the Shanghai Science and Technology Commission (18XD1401200), and the Young Talented Specialist Training Program of Shanghai.

Conflict of interest

The authors declare no conflicts of interest.

References (70)

  • B.C. Ozdemir et al.

    Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival

    Cancer Cell

    (2014)
  • A.D. Rhim et al.

    Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma

    Cancer Cell

    (2014)
  • K.J. Roberts et al.

    The stromal niche for epithelial stem cells: a template for regeneration and a brake on malignancy

    Cancer Cell

    (2017)
  • V.G. Cooke et al.

    Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway

    Cancer Cell

    (2012)
  • J. Gore et al.

    Pancreatic cancer stroma: friend or foe?

    Cancer Cell

    (2014)
  • R.L. Siegel et al.

    Cancer statistics, 2018

    CA Cancer J. Clin.

    (2018)
  • D.P. Ryan et al.

    Pancreatic adenocarcinoma

    N. Engl. J. Med.

    (2014)
  • H.A. Burris et al.

    Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial

    J. Clin. Oncol.

    (1997)
  • T. Conroy et al.

    U. Groupe Tumeurs Digestives of, P. Intergroup, FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer

    N. Engl. J. Med.

    (1817-1825)
  • D.D. Von Hoff et al.

    Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine

    N. Engl. J. Med.

    (2013)
  • V. Heinemann et al.

    Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO-PK0104)

    Gut

    (2013)
  • M.J. Moore et al.

    G. National Cancer Institute of Canada Clinical Trials, Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group

    J. Clin. Oncol.

    (1960-1966)
  • M. Sinn et al.

    CONKO-005: adjuvant chemotherapy with gemcitabine plus erlotinib versus gemcitabine alone in patients after R0 resection of pancreatic cancer: a multicenter randomized phase III trial

    J. Clin. Oncol.

    (2017)
  • C. Feig et al.

    The pancreas cancer microenvironment

    Clin. Cancer Res.

    (2012)
  • W.Q. Wang et al.

    Infiltrating immune cells and gene mutations in pancreatic ductal adenocarcinoma

    Br. J. Surg.

    (2016)
  • A. Neesse et al.

    Stromal biology and therapy in pancreatic cancer

    Gut

    (2011)
  • M.H. Sherman et al.

    Stromal cues regulate the pancreatic cancer epigenome and metabolome

    Proc. Natl. Acad. Sci. U. S. A.

    (2017)
  • M. Waghray et al.

    GM-CSF mediates mesenchymal-epithelial cross-talk in pancreatic cancer

    Cancer Discov.

    (2016)
  • E. Pure et al.

    Can targeting stroma pave the way to enhanced antitumor immunity and immunotherapy of solid tumors?

    Cancer Immunol. Res.

    (2016)
  • C.M. Sousa et al.

    Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion

    Nature

    (2016)
  • D. Ohlund et al.

    Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop

    BMC Cancer

    (2013)
  • H. Laklai et al.

    Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

    Nat. Med.

    (2016)
  • M.F. Nielsen et al.

    Key players in pancreatic cancer-stroma interaction: cancer-associated fibroblasts, endothelial and inflammatory cells

    World J. Gastroenterol.

    (2016)
  • A. Lo et al.

    Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells

    Cancer Res.

    (2015)
  • D.T. Fearon

    The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance

    Cancer Immunol. Res.

    (2014)

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    These authors contributed equally to this work.

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