June 1, 2021
The importance of systemic networks in cancer treatment
1 June 2021
Cancer is a systemic disease. This means it is important to treat not just the obvious tumor
mass but also the systemic cellular networks that nurture the tumor. Surprisingly, most
cancer treatment plans ignore the systemic networks.
Targeting systemic tumor networks will be difficult, requiring combinations of combinations of
therapy. We will need different therapeutic strategies for the primary tumor and many of the
systemic networks. Each type of therapy may need to consist of combinations of treatments
to block a sufficient number of steps in the web-like pathways that exist for each cellular
This subject was discussed in the abstract below, which was not accepted at a recent
conference. Although disappointing, the advantage of this rejection is that I can publish it
now without any copyright restrictions. The full paper is at
http://www.natpernick.com/PancreaticcancerFeb2021.html. Please send your comments
to Nat@PathologyOutlines.com.
Monitoring Dysfunctional Networks To Support Curative Treatment of Pancreatic
March 2021
Nat Pernick, M.D., Nat@PathologyOutlines.com
Context: Pancreatic cancer is a systemic disease with dysfunctional networks that must be
treated and monitored, in addition to the primary tumor.
Design: We calculated the population attribution fraction of pancreatic cancer risk factors
and reviewed their mechanisms of action within the context of complexity theory to determine
common features, principles of curative therapy and key network issues.
Results: Random chronic stress causes 25-35% of cases, non O blood group 17%, excess
weight 15%, cigarette smoking 15%, type 2 diabetes 9%, alcohol 5%, diet 5%, family history
/ germline 2% and chronic pancreatitis 1% (Table 1). Risk factors can be categorized into 5
“super promoters”: chronic inflammation, DNA alterations, random chronic stress / bad luck,
immune system dysfunction (individual or “societal”) and hormones. We identified key
systemic network issues that curative therapy must address and propose monitoring their
response to treatment: overall inflammatory process, immune system’s antitumor
capabilities, microenvironment (vasculature, inflammation, fibroblasts, extracellular matrix) of
tumor and metastatic sites, activation of unicellular-like networks, activation of embryonic
networks, insulin-IGF system and germline networks that promote malignant behavior.
Pathologists must create assessments of each key network’s response to treatment by
determining relevant biomarkers to measure and understanding how their expression affects
treatment and survival. Developing a cancer network score analogous to the TNM score may
be useful.
Conclusions: Pancreatic cancer has an altered systems biology with changes in systemic,
nontumor networks that typically will not revert to normal by destroying the original tumor.
Curative therapy requires treatment targeting these networks and monitoring their response
to treatment.
Table 1 – Pancreatic cancer risk factors
Risk factor Attributable fraction
Random chronic stress 25-35%
Non O blood group 17%
Excess weight 15%
Cigarette smoking 15%
Type 2 diabetes 9%
Alcohol use 5%
Diet 5%
Family history / germline 2%
Chronic pancreatitis 1%
Table 2 – Cancer “super promoters”
Chronic inflammation
DNA alterations
Random chronic stress / bad luck
Immune system dysfunction (individual or “societal”)
Table 3 – Key systemic network issues
Overall inflammatory process
Immune system’s antitumor capabilities
Microenvironment (vasculature, inflammation, fibroblasts, extracellular matrix) of tumor and
metastatic sites
Activation of unicellular-like networks
Activation of embryonic networks
Insulin-IGF system
Germline networks that promote malignant behavior