Kenneth J. Pienta, Department of Internal Medicine and Cancer Center, the University of Michigan, Ann Arbor, MI  48109; kpienta@umich.edu

An example of a tumor ecosystem. Prostate cancer cells growing in the bone microenvironment are in contact with over 30 normal host cells as well as the inorganic bone matrix at any given time.

The traditional view of a tumor is that of a mass of growing cancer cells pushing all of the normal host cells out of the way as it takes over an organ.  This could not be farther from the truth. There has been an increasing recognition that the tumor microenvironment contains host non-cancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with non-tumor cells, and the cancer cells may compete and/or cooperate with each other. We have demonstrated that over 50% of the cells in a tumor mass are actually normal host cells (1).  It has been demonstrated that these interactions can alter the genotype and phenotype of the host cells as well as the cancer cells. The interaction of these cancer and host cells to remodel the normal host organ microenvironment may best be conceptualized as an evolving ecosystem (2). Describing tumors as ecological systems defines new opportunities for novel cancer therapies (“ecological therapy”). The ecology literature is filled with stories of how changing the ecosystem resulted in the death of a species.  A key method, therefore, to kill cancer cells in the tumor ecosystem may be to inhibit other cell species within the environment that are supporting the growth and survival of cancer cells.

One example of this is target tumor associated macrophages (TAMs). TAMs promote tumor growth by stimulating angiogenesis and matrix remodeling. Since they are not normally present in the bone microenvironment, they can be considered invasive or facilitative species in the tumor ecosystem.

Among the identified 50 human chemokines, chemokine (C-C motif) ligand 2 (CCL2) is of particular importance in cancer development since it serves as one of the key mediators of interactions between tumor and host cells. In the bone marrow microenvironment, CCL2 is produced by osteoblasts, osteoclasts, and endothelial cells and induces the recruitment of monocytes to the tumor and their subsequent differentiation into TAMs.  Multiple studies have revealed that inhibition of CCL2 substantially decreases macrophage infiltration, decreases osteoclast function, and inhibits prostate cancer growth in bone in preclinical animal models (3). We utilized these preclinical data and have successfully translated ecological therapy to the clinic. SWOG study S0916, for example, was a phase II, window trial of an anti-CCL2 receptor antibody in patients with bone metastases. This biomarker driven study was designed to test the hypothesis that inhibiting CCL2 in patients with cancer metastatic to bone would inhibit monocyte/TAM/osteoclast function. This was measured by changes in osteoclast function as a decrease in the bone turnover marker urinary N-telopeptide (uNTX) by 25% or more from baseline. Results demonstrated decreases in urinary NTX in a significant number of patients.

These data suggest that altering the tumor microenvironment through inhibition of CCL2 may be a viable strategy for interfering with cancer cell activity and growth and we continue to pursue this in clinical trials.  Multiple other examples of disrupting the tumor ecosystem for cancer therapy exist, including blocking angiogenesis to inhibit blood vessel growth, blocking osteoclasts to inhibit bone remodeling, and stimulating the immune system to attract new predators to the microenvironment of the cancer (4).

It is rare that a single therapeutic agent can cure a patient with cancer because of innate cancer cell resistance and tumor cell heterogeneity.  Ecotherapy offers the option of targeting host facilitating cells simultaneously with the cancer cells.

 

References

1.         Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009 Dec 4;284(49):34342-54. PMID:19833726

2.         Pienta KJ, McGregor N, Axelrod R, Axelrod DE. Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments. Transl Oncol. 2008 Dec;1(4):158-64. PMID:19043526

3.         Loberg RD, Ying C, Craig M, Day LL, Sargent E, Neeley C, Wojno K, Snyder LA, Yan L, Pienta KJ. Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res. 2007 Oct 1;67(19):9417-24. PMID:17909051

4.         Camacho DF, Pienta KJ. Disrupting the networks of cancer. Clin Cancer Res. 2012 May 15;18(10):2801-8. PMID:22442061