Curing Cancer - Part 6 - Key systemic network issues
21 January 2021
This is my sixth essay about curing cancer based on the principles of complexity theory - follow my blog at . This essay proposes strategies for curative therapy regarding key systemic networks other than those affecting the primary tumor, which were discussed in .
1. Disrupt the inflammatory process that plays a central role in promoting and sustaining carcinogenesis. Tumors have been described as wounds that do not heal (, ). Activation of the inflammatory system, which promotes wound healing and accompanies many malignancies (, ), has been considered a major cause of cancer since 1863, when Virchow speculated that some irritants enhance cell proliferation through tissue injury and chronic inflammation (). Inflammation is activated by many cancer risk factors, including excess weight, cigarette smoking, heavy alcohol consumption, aging and a Western diet (high fat, highly processed foods, low consumption of vegetables, fruits and whole grains) (, ).
Inflammation may play a central role in promoting carcinogenesis because it is widely connected to other networks and is unstable as it rapidly initiates sophisticated repair, antimicrobial and antitumor processes. Ultimately, this network instability may propagate to local and systemic networks and promote malignancy ().
Cancer disrupts the usual coordination of inflammatory networks. Sophisticated biologic processes, such as inflammation and embryogenesis, require coordination of activity, since isolated network activity by itself can be either useful or destructive, depending on its context. For inflammation, this coordination includes triggering both the process and its resolution at the same time (, ). As the trauma is repaired or the threat from foreign organisms subsides, the resolution pathways cause networks to revert towards their initial states to prevent bystander damage to tissue (). Cancer risk factors may also trigger the inflammatory process but through nonconventional means that do not simultaneously initiate the resolution process (). This causes persistent inflammation, which may wear down stabilizing factors in inflammatory and adjacent networks, particularly when accompanied by other risk factors, which further drives the malignant process (, ).
Curative cancer therapy needs to antagonize or diminish this persistent inflammatory process. Suggested options include: (a) triggering pro-resolution pathways (, ); (b) using anti-inflammatory agents to diminish inflammation in general (, ); (c) mimicking the halting mechanisms associated with wound healing (, ) and liver regeneration (); and (d) countering germline (inherited genetic) changes that promote instability in the inflammatory process.
2. Disrupt the microenvironment that nurtures tumor cells at primary and metastatic sites. Cancer risk factors produce a microenvironment that nurtures mutated cells, steers cellular networks towards malignant pathways (), helps them escape immune surveillance () and ultimately promotes invasion by activating cells to mimic physiologic “invasion” of wounded epithelium through the extracellular matrix (, ). Tumors require a fertile “soil” for the cancer “seeds” to grow (, ). For example, Hodgkin Reed-Sternberg cells produce cytokines that assist the survival and proliferation of lymphoma cells () and pancreatic tumor cells produce cytokine IL1β and proinflammatory factors that establish a tumor supportive microenvironment (, ). From a network perspective, there is a complex crosstalk among cancer cells, host cells and the extracellular matrix ().
Curative treatment should disrupt or normalize the microenvironment by targeting inflammation, the vasculature and the extracellular matrix (). For example, anti-VEGF or anti-VEGF receptor treatment can normalize vasculature by reducing vascular permeability (). Normalizing the microenvironment may also enhance drug delivery and effectiveness (, ) or make existing tumors or intermediate states more susceptible to immune system attack ().
It is also important to disrupt the microenvironment of possible metastatic sites. Typically, tumor cells die at secondary sites but the malignant process preconditions the otherwise hostile microenvironment of the secondary site so it can sustain their colonization (, ).
3. Disrupt the microenvironment that promotes embryonic features associated with aggressive tumor behavior. In the microenvironment of the fertilized egg, coordinated network activity ultimately moves embryonic related networks towards mature, differentiated phenotypes in the fetus and newborn. However, cancer risk factors stimulate these networks in a non coordinated manner to trigger embryonic properties such as rapid cell division (), cell migration (, ) and changes to cell differentiation () that do not mature over time.
Curative treatment should include agents to promote this maturation, such as retinoids used in acute promyelocytic leukemia (), myeloid differentiation promoting cytokines (), cancer cell reprogramming drugs (, ) or possibly agents that halt rapid cell division in embryogenesis ().
4. Repair the immune system dysfunction that coevolves with carcinogenesis. The immune system consists of a web of interacting networks whose effectiveness is systematically degraded with malignant progression. Immune dysfunction in cancer is typically not just the failure of one particular pathway (). Curative treatment should attempt to improve immune system function with combinatorial therapy that targets multiple aspects of immune dysfunction ().
5. Promote the activation of gene networks supporting stable, multicellular processes and suppress networks promoting unicellular processes that support malignant type behavior. Multicellular organisms evolved from unicellular organisms by adding new genes and more intricate controls to existing networks for metabolism and replication (, ). This enables greater communication and coordination between cells and makes possible higher level functions, such as cell differentiation and programmed cell death (). The new control mechanisms keep cellular and systemic processes on track and shift the survival focus from individual cells towards the organism as a whole (). The operation of multicellular and unicellular programs appears to be somewhat mutually exclusive. Inflammation and DNA alterations may damage these multicellular controls, activating the existing genetic toolkit of preprogrammed, malignant behavior in unicellular networks based on what has been described as the atavism hypothesis of cancer (, , ).
To restore the balance between multicellular and unicellular controls, curative treatment should activate different components of multicellular networks (, ). In addition, treatment could target the weaknesses of cancer cells by applying a specific cellular stress that is readily dealt with by healthy cells using evolved capabilities or multicellular programming but not by cancer cells with predominantly unicellular programming (). This includes “lethal challenges” of high dose methotrexate with leucovorin rescue () or targeting other aspects of chaotic or unstable states, such as cell-extracellular matrix detachment ().
6. Target the hormones that may promote tumor growth. Physiologic (i.e. normal) levels of estrogens and androgens and elevated levels of insulin are associated with breast (), endometrial / uterine (), prostate () and pancreatic cancer (, , ). The primary mechanism may involve promotion of cell growth, particularly at a stage when these cells are particularly vulnerable to instability.
Simple antagonism of hormonal pathways is possible using tamoxifen for estrogens, antiandrogens for testosterone and metformin for insulin (). One block in these networks is apparently adequate for normalization, in contrast to the 3-5 blocks required for other tumor cell networks. Behavioral changes, such as weight loss, exercise, a healthier diet and reducing alcohol and tobacco use may also be therapeutic by either altering hormone levels or changing their interaction with other risk factors.
7. Antagonize germline changes that promote malignant behavior. Genetic testing of nontumor cells (germline testing) is recommended for all patients with pancreatic cancer () and select patients with other cancers or family histories of cancer (, ). Results are currently used to determine antitumor therapy () as well as for cancer screenings, reproductive choices and genetic counseling. We suggest using these results to also provide treatment that: (a) moves premalignant or malignant cells into less harmful pathways as discussed in Part 5; or (b) counters common germline changes in inflammatory, DNA repair, cell cycle stability, immune system or other networks that promote malignancy.
These blog essays have summarized proposed strategies for curative cancer therapy. The next essay will discuss random chronic stress, a newly proposed major factor in how cancer arises that cannot be prevented but can be better understood.