Stromal biology and therapy in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.
Neesse
Albrecht
A
Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge, UK.
Michl
Patrick
P
Frese
Kristopher K
KK
Feig
Christine
C
Cook
Natalie
N
Jacobetz
Mike A
MA
Lolkema
Martijn P
MP
Buchholz
Malte
M
Olive
Kenneth P
KP
Gress
Thomas M
TM
Tuveson
David A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology*; D059016:Tumor Microenvironment / Q000502:physiology
D000970:Antineoplastic Agents