Study Evaluates Obesity-Related Factors Leading to Pancreatic Cancer Progression

MedicalResearch.com Interview with:

Joao Incio MD Research Fellow in Radiation Oncology Harvard Medical School/MGH Boston, MA

Dr. Joao Incio

Joao Incio MD
Research Fellow in Radiation Oncology
Harvard Medical School/MGH
Boston, MA

MedicalResearch.com: What is the background for this study?

Dr. Incio: With  the  current  epidemic  of  obesity,  the  majority  of  pancreatic  cancer  patients  are  overweight  or  obese  at  diagnosis.  Importantly, obesity  worsens treatment  outcomes  in  pancreatic  cancer  patients.  Therefore,  understanding  the  mechanisms  that  underlie  the  poorer  prognosis  of  obese  cancer  patients  is  of  paramount importance.  Obesity  causes  inflammation  and  fibrosis  in  the  normal  pancreas  due  to  the  accumulation  of  dysfunctional  hypertrophic  adipocytes.  Importantly,  desmoplasia  -­  a fibroinflammatory  microenvironment  -­  is  a  hallmark  of  pancreatic  ductal  adenocarcinoma  (PDAC),  and  we  have  shown  that  activation  of  pancreatic  stellate  cells  (PSCs)  via angiotensin-­II  type  1  receptor  (AT1)  pathway  is  a  major  contribution  to  tumor  desmoplasia.  Whether  obesity  affects  desmoplasia  in  PDACs,  and  interferes  with  delivery  and response  of  chemotherapeutics,  was   the focus of our study.

MedicalResearch.com: What are the main findings?

Dr. Incio: We  found  that  obesity  aggravates  desmoplasia  in  PDACs  in  both  patient  samples  and  multiple  mouse  models.  In  addition,  tumors  in  obese  mice  presented  with elevated  levels  of  activated  PSCs  and  fibrosis,  as  well  as  inflammatory  cytokines  and  tumor-associated neutrofils (TANs).  These  alterations  in  the  tumor  microenvironment  in  obesity  associated  with accelerated  tumor  growth,  reduced  tumor  blood  perfusion  and  increased  hypoxia,  and  impaired  delivery  and  efficacy  of  chemotherapeutics.  Genetic  ablation  and pharmacological  inhibition  (losartan)  of  AT1  signaling  reversed  obesity-­augmented  desmoplasia  and  tumor  growth,  and  improved  the  response  to  chemotherapy  to  the  level observed  in  lean  mice.

We  further  discovered  the  underlying  mechanisms:

1)  obesity  increases  intra-­tumor  adipocytes  and  IL-­1ß  secretion  by  these  cells;
2)  increased  IL-­1ß induces  TAN  recruitment;
3)  recruited  TANs  activate  PSCs;  and
4)  activated  PSCs  enhance  desmoplasia.

Conversely,  activated  PSCs  also  secrete  IL-­1ß  that  recruits  further TANs.  Of  clinical  relevance,  we  found  that  metformin  not  only  normalizes  the  abnormal  systemic  metabolism,  but  also  reprograms  PSCs  and  immune  cells  and  alleviates the  fibroinflammatory  microenvironment  in  pancreatic  cancer  in  obesity/diabetes.  Importantly,  the  strategies  described  above  were  not  effective  in  the  normal  weight  setting.

MedicalResearch.com: What should clinicians and patients take away from your report?

Dr. Incio: We successfully  demonstrated  that  targeting  desmoplasia,  including  immunomodulation  with  anti-­IL-­1ß,  or  treatment  with  generic  drugs  such  as  losartan and  metformin  are  potential  strategies  to  potentiate  treatments  in  PDAC  patients  with  excess  weight. Prospective studies with these drugs are warranted.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Incio: Additional pharmacological agents that target the obesity-related factors should be evaluated. In addition, it appears that obesity causes immunosupression in the microenvironment, therefore immunotherapy may also be a possible intervention to prevent obesity-induced tumor progression.

Citation: AACR Abstract Apr 17, 2016,

Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy
Joao Incio1, Priya Suboj1, Shan M. Chin1, Chen Ivy1, Mei Ng1, Hadi Nia1, Jelena Grahovac1, Hao Liu1, Shannon Kao1, Suboj Babykutty1, Yuhui Huang1, Keehoon Jung1, Nuh Rahbari1, Xiaoxing Han1, Vikash Chauhan1, John Martin1, Julia Kahn1, Peigen Huang1, Raquel Soares2, Yves Boucher1, Dai Fukumura1, Rakesh Jain1. 1Harvard Medical School/MGH, Boston, MA; 2FMUP, Portugal

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