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Page 24 of 31 Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63

“HORIZONTAL” VS. “VERTICAL” APPROACHES
Modalities to target cancer at the cellular level (i.e., tyrosine kinase inhibitors and antibodies directed
to the antigens present on the surface of the cancer cells) have been already in place now for almost
two decades. Immunotherapies with checkpoint inhibitors and CAR-T cell approaches have recently
improved the quality and duration of life of many cancer patients. We envision that agents targeting the
systemic hallmarks of cancer and interrupting the communication between the different components of
the cancer system will represent the “new wave” of cancer treatments. In the multi-scale model of cancer
a “horizontal” approach is considered targeting the cross-talk between the different components of the
CISPN and blocking the communication between its parts and a “vertical” approach would use drugs that
act simultaneously at the cellular, tissular and systemic level in a particular sub-component of the CISPN.
An example of a “horizontal” approach is the finding that the blockade of the CXCL5/7 receptor CXCR2, or
the transient depletion of either platelets or granulocytes, prevents the formation of early metastatic niches
and significantly reduced metastatic seeding and progression [123] . Granulocyte recruitment depends on the
secretion of CXCL5 and CXCL7 chemokines by platelets upon contact with tumor cells [123] . An example of
a “vertical” approach using trans-level drugs acting simultaneously at the cellular, tissular and organismic
levels simultaneously is the use of beta-blockers. Some beta-blockers, for example, like propranolol, at
the tissular level have an immunomodulatory effect [248] and at the organismic level alter the metastatic
potential of cancer cells [208] . A group of researchers at Penn State University found that melanoma patients
who received immunotherapy while taking pan β-blockers lived longer than patients who received
immunotherapy alone or patinets that received immunotherapy and β1-selective blockers [249] . In a follow-
up experiment with mice, the researchers saw the same results [249] . Bisoprolol is another selective β1-blocker
commonly used to treat hypertension, cardiac ischemia, and congestive heart failure. Bisoprolol improved
survival, increased total heart mass, and other heart parameters and, importantly, improved food intake
and activity levels in an AH-130 tumor-bearing rats model [250] . Clinical studies with Bisoprolol are planned
in patients with cancer cachexia (Professor Anker, Charité Hospital, Berlin, personal communication).

CONCLUSION
Cancer is a multidimensional process with specific characteristics at the cellular, tissular and the organismic
level. Basic research and clinical data obtained over the last decade suggests that, at the macroscopic level,
cancer behaves like an evolving co-dependent system that interacts continuously through CISPN with the
modified body systems. Cancer cells and cancer stroma secreted exosomes, cytokines and other soluble
factors together with the modified, cancer-supporting body systems, are responsible for establishing the
CISPN and the systemic hallmarks of cancer. Without taking into consideration this larger, organism-
level picture, some of the current local treatments targeted towards the cancer cells or tissues may lead
to cancer progression. For example, in some cases of head and neck cancer, (up to 29% in some series),
checkpoint inhibitor treatments may induce cancer hyperprogression [251] . Treatments targeted towards the
cancer system and the systemic hallmarks of cancer are urgently needed. Moving to the organismic level
and targeting the systemic hallmarks of cancer in concerted therapeutic approaches with currently existing
therapies may further improve our cancer armamentarium in the immediate future.

DECLARATIONS
Authors’ contributions
The author solely contributed to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
Not applicable.