TY - JOUR
T1 - Stroma-targeting strategies in pancreatic cancer
T2 - Past lessons, challenges and prospects
AU - Polani, Faran
AU - Grierson, Patrick M.
AU - Lim, Kian Huat
N1 - Publisher Copyright:
© 2021 Baishideng Publishing Group Co., Limited. All rights reserved.
PY - 2021/5/14
Y1 - 2021/5/14
N2 - 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 shorterlived. Aside from typically harboring genetic alterations that to date remain undruggable 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 stromatargeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.
AB - 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 shorterlived. Aside from typically harboring genetic alterations that to date remain undruggable 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 stromatargeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.
KW - Cancer-associated fibroblasts
KW - Clinical trials
KW - Pancreatic cancer
KW - Stroma
KW - Treatment resistance
UR - http://www.scopus.com/inward/record.url?scp=85105882682&partnerID=8YFLogxK
U2 - 10.3748/wjg.v27.i18.2105
DO - 10.3748/wjg.v27.i18.2105
M3 - Review article
C2 - 34025067
AN - SCOPUS:85105882682
SN - 1007-9327
VL - 27
SP - 2105
EP - 2121
JO - World Journal of Gastroenterology
JF - World Journal of Gastroenterology
IS - 18
ER -