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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

2 Responses to “Targeting the tumor ecosystem, by Kenneth Pienta”

  1. Arthur Saniotis says:

    This insightful article clearly underpins Gregory Bateson’s thesis of relationality – how we need to re-assess natural systems in terms of relations instead of individual entities. Scientists such as Lynn Margulis have also highlighted the central role of symbiotic relations within nature. Understanding cancer as an ecosystem will offer scientists a new observational window. It is perhaps no surprise that the ‘competition’ view of cancer has been popularised in medical science, since many western societies are governed by ‘dominator’ principles which still inform the practice of science.

  2. RE: A critical Review on “Targeting the tumor ecosystem”: Why couldn’t We (oncologists, clinicians, scientists, biomedical reviewers, critics, etc) be more specific and forthright about Targeting the tumor ecosystems of today and beyond!? — Or, Targeting which tumor-specific ecosystems: The primary or the metastatic tumor ecosystems!?

    Preamble: First, let me compliment on Kenneth Pienta and his colleagues, for their (apparently) novel (but inherently-misconstrued, and misattributed, their otherwise specific) anti-tumor stromal elements as “ecological therapy” (or ET; instead of the more appropriate “ecological pathogenesis” terminology of “tumor ecosystems”) — and — their otherwise very specifically-targeted “anti-CCL2 (chemokine ligand 2/monocyte recruiter) therapeutic” effects and concepts: whereby the “targeted therapy” (not the misattributed ET concept) which is currently being tested in clinical trials (such as, the SWOG study S0916, in phase II trials) in critical attempting to eradicate the last (possibly) metastatic tumor cells — particularly those specific monocyte-transformed TAMs (tumor associated macrophages) and tumor cells, that have had metastasized to, and seeded in, bones — of their prostate cancer (PC) patients!? Thus, I thought the above Pienta’s very abbreviated (especially in modern oncology and biotherapeutic concepts) but intriguing (so-called) ET article, could have had been more appropriately and forthrightly entitled “Metastatic Prostate Cancer-to-Bone: Targeting the Tumor Ecosystem”!?

    1] From our modern biomedical research and development (R&D) perspective: Especially in the evermore specialized, disease-targeted, focused, and personalized medicine (PM) era of today and beyond; and in the evermore specific pathogenetically-defined, elaborated, and individualized cancer therapy (ICT) nowadays, the evermore etiologically-targeted PM-translated and specialized biomedical R&D pursuits and therapeutic concepts, in clinical and preclinical trials (in and for any targeted ICT and in and for any given tumor systems since the 1980s) must First be clearly and elaborately analyzed, specified, identified, classified, and diagnosed or spelled out, in totality and in advance, and categorically-based on the following: a) characterizing and qualifying their each tumor-associated therapeutic targets (including any other stromal effects, etc) in and for any specific tumor types, tumor-stromal systems, growth and development conditions (primary and/or metastatic in etiology or pathogenesis) in totality and in advance; b) following and focusing on their each specifically-targeted, screened, identified, and tested anti-tumor (and/or anti-tumor-associated stromal factors, including angiogenesis, TAMs, etc) concepts and protocols, in and for their each respective tumor model-systems; and c) all these biomedical R&D standards and practices are to be fully pursued in accordance with their each specified and/or prescribed preclinical and clinical screening and testing rules, concepts, and guidelines in the labs — be it in the academic or industrial R&D settings, worldwide, since the 1980s!?

    2] Whereas in the ET concepts and protocols as outlined above (specifically-designed or elaborated in and for a PC metastatic-to-bone ecosystem): It seems the specifically-targeted anti-CCL2/anti-TAMs therapeutic model-system, has had been exclusively directed to eliminate the autologous* — not heterologous* — bone metastases (or micro tumor-stroma ecosystems) of the PC patients, alone!? As it seems a) Not to be targeting any specific treatments to the autologous “primary” (or spontaneously-arising) PC micro ecosystems, at all; b) Nor to be indicating any specific treatments to the metastatic PC-stroma ecosystems, that might have had seeded elsewhere, in or at any other autologous organ sites or tissue systems, at all; and above all, it seems c) Not to be critically concerning or including the generally-required cross-screening and/or testing of the anti-tumor ecosystem-specificity (especially the anti-CCL2/TAMs specificity or cross-tumor ecosystems reactivity tests) in and for any other similarly-tested biotherapeutics, in and on any other tumor cell types* (including any other peritoneal cancer metastases to bones, etc) and/or in/on any other tumor ecosystems (primary or metastatic in origin) within an autologous cancer patient, as well!?

    [*Histologically, cytologically, pathologically, immunologically, and biomedically speaking: The term “cell types” is more biogenetically-defined than the “ecological” or elusive term of “cell species” -- as ones that have had been otherwise mischaracterized in ET theory above (!?) -- so as to accurately infer to the fact, that in any PM-specified ICT -- not the misattributed ET concept -- in and for any tumor systems (primary or metastatic in pathogenesis) as ones that have had been etiologically or oncologically identified, classified or diagnosed; and as ones that have had been referring to the spontaneously-occurring, and/or later metastasizing, tumors -- all arising within the same “genetically-autologous” cancer patient-body system, of course -- whereas the generally ecologists or naturalists (or especially the neo-Darwinists or biogenetic-reductionists) misuse of the ecological term of “cell species” could easily -- and would -- otherwise “biogenetically” confuse, unduly complicate, and indeed, it has had misattributed the otherwise inherently-autologous “cell types” (including normal and/or autologous tumor cells) to an otherwise “genetically-heterologous” or “ecologically-mixed” population of “cell species” in and within an otherwise-intact (or autologous) cancer patient-body system!?]

    3] As such, within our concurrent biomedical, specific immunological, and oncological histocompatibility and biotherapeutic context; and from the perspective of the novel PM-translated ICT concepts and practices (especially since the 1960s-80s), such a grossly-generalized or broadly-misattributed ET or “ecological therapy” above as one that has had been attempting to devise a very specific anti-micro-tumor-ecosystem therapy (while without any cross-testing in and for any other tumor cell types and/or metastases in any other organ sites, etc) may Not be universally translated nor applicable to any other cancer ecosystems, at all (!?) — lest the above ET (specifically-devised in and for a metastatic PC-to-bone) concepts and protocols, could be further categorically analyzed, tested, identified, specified, characterized, elaborated, differentiated, and established (especially in and for any other possible tumor cell types, disease biogenetic ecosystems, therapeutic classifications, etc) by and within our concurrent biogenetic R&D and biomedical oncology terms, as follows: a) the primary or the metastatic tumor ecosystems; b) the autologous or the heterologous biogenetic therapeutics (such as anti-CCL2/TAMs antibodies: which are mostly heterologously-derived or raised xenogenically in animals other than the PC patients themselves); and last, but not least, c) the primary or the metastatic-collaborators or tumor-associated enablers (such as TAMs, monocytes, osteoclasts, etc: which are certainly and inherently-autologous in and within the PC patients themselves); etc (see Comment 1 above)!?

    Thus, critically I would certainly wonder if the above Pienta’s apparently-novel ET concepts and protocols (specifically-focused and developed in and for the metastatic PC-to-bone alone) could be (at once) generalized and/or applied to any other tumor-specific PM-translated ICT, as well; whereby such a specific “anti-CCL2/TAMs-translated or targeted therapy” may soon be further inquired and considered, in and for any other potentially-metastatic tumor cell types-to-bones to emulate, test, identify, strategize, or model on: all elaborative and specific anti-tumor and/or anti-tumor-associated stromal characterization and identification of the biotherapeutic ET concepts, protocols, effects, and criteria, are to be modified and/or incorporated in full accordance with their each respective tumor types, tumor ecosystems, disease growth and development conditions, of course — as I duly outlined in my recent review of the specific genomic-based ICT above (see Comment 1 above)!?

    Best wishes, Mong 11/12/12usct3:27p; practical science-philosophy critic; author “Decoding Scientism” and “Consciousness & the Subconscious” (works in progress since July 2007), Gods, Genes, Conscience (iUniverse; 2006) and Gods, Genes, Conscience: Global Dialogues Now (blogging avidly since 2006).

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