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World J Gastroenterol. May 14, 2021; 27(18): 2105-2121
Published online May 14, 2021. doi: 10.3748/wjg.v27.i18.2105
Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects
Faran Polani, Patrick M Grierson, Kian-Huat Lim
Faran Polani, Patrick M Grierson, Kian-Huat Lim, Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, United States
Author contributions: Polani F, Grierson P and Lim KH contributed to the concepts, performed literature review, drafted the manuscript, and approved the final manuscript; Polani F and Lim KH drew the figure using BioRender.
Supported by National Institutes of Health/National Cancer Institute, No. 5R37CA219697-01 (to Lim KH); American Cancer Society, No. RSG-17-203-01-TBG (to Lim KH); and Alvin J. Siteman Cancer Center Siteman Investment Program (from Barnard Trust and The Foundation for Barnes-Jewish Hospital) (to Lim KH); and Emerson Collective Grant (to Grierson PM).
Conflict-of-interest statement: The authors have declared no conflict of interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Kian-Huat Lim, MD, PhD, Associate Professor, Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110, United States. klim@dom.wustl.edu
Received: January 8, 2021
Peer-review started: January 8, 2021
First decision: February 23, 2021
Revised: March 9, 2021
Accepted: April 21, 2021
Article in press: April 21, 2021
Published online: May 14, 2021
Processing time: 121 Days and 13.8 Hours
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance. However, emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes. These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression. The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells, stromal fibroblasts, and immune cells. This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease. Here, we provide a concise review on lessons learned from past stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.

Keywords: Stroma; Pancreatic cancer; Treatment resistance; Cancer-associated fibroblasts; Clinical trials

Core Tip: Stromal desmoplasia is not only a prominent histological hallmark of pancreatic cancer, but also a biological barrier to therapies. Various strategies aimed at targeting the stroma to improve therapeutic outcomes have been largely unsuccessful. Here we comprehensively reviewed the rationales and lessons learned from various stromal-targeting strategies and provide prospects on improving these approaches in future clinical trials.