Ecological therapy for cancer: defining tumors using an ecosystem paradigm suggests new opportunities for novel cancer treatments

Abstract

We propose that there is an opportunity to devise new cancer therapies based on the recognition that tumors have properties of ecological systems. Traditionally, localized treatment has targeted the cancer cells directly by removing them (surgery) or killing them (chemotherapy and radiation). These modes of therapy have not always been effective because many tumors recur after these therapies, either because not all of the cells are killed (local recurrence) or because the cancer cells had already escaped the primary tumor environment (distant recurrence). There has been an increasing recognition that the tumor microenvironment contains host noncancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with nontumor cells, and the cancer cells may compete and/or cooperate with each other. 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. In classic terms, an ecosystem describes the physical and biological components of an environment in relation to each other as a unit. Here, we review some properties of tumor microenvironments and ecological systems and indicate similarities between them. We propose that describing tumors as ecological systems defines new opportunities for novel cancer therapies and use the development of prostate cancer metastases as an example. We refer to this as "ecological therapy" for cancer.

Figure 1

Darwinian evolution and cancer. Cancers evolve by darwinian principles that include clonal proliferation, mutational changes within the clonal population resulting in genetic diversity, and selection pressures leading to proliferation of subclones that bridge bottlenecks such as lack of nutrients and space limitations. (A) In the traditional view of tumor progression, there is competition between genetically unstable, partially transformed, proliferating cells. The cells compete for limited oxygen, essential nutrients, and growth factors, and therefore, many die. Eventually, one cell accumulates sufficient mutations to express all of the functions required for a clone of fully malignant cells to emerge as a successful species occupying an environmental niche. This founder cell can be the result of selective pressures as indicated by the bottlenecks or the result of intrinsic genetic instability leading to a full complement of mutations that are required for full malignant potential. The bottlenecks indicate where a new dominant cell type becomes apparent. (B) In addition, we have hypothesized a tumor progression model based on the theory of cooperation. Genetically unstable partially transformed cells proliferate and yield different mutant cell types. The different cell types cooperate with each other, enabling them to survive and proliferate. The concept of cooperation among partially transformed cells is added to the traditional view of tumor progression. As in the traditional view, eventually one cell may accumulate sufficient mutations to express all of the functions required for a clone of fully malignant cells to emerge as the dominant species. Adapted from (A) Greaves [6] and Axelrod et al. [5].

Figure 2

The prostate cancer bone metastasis ecosystem. Prostate cancer cells (C) in the bone metastasis ecosystem are in close proximity and/or contact with a variety of cell types, each of which can be considered a species based on their similarities in morphology and function. These cell types include hematopoietic stem cells (HS), mesenchymal stem cells (MS), endothelial cells (E), pericytes (P), fibroblasts (F), macrophages (M), T lymphocytes (T), B lymphocytes (B), dendritic cells (D), adipocytes (A), neurons (N), osteoclasts (Oc), osteoblasts (Ob), megakaryocytes (Mk), neutrophils (Ne), and eosinophils (Eo). All of these cell species are interacting with the soluble and insoluble factors that make up the biotope of the bone microenvironment. Insoluble factors include the collagen and pyrophosphate of the bone extracellular matrix. Soluble factors include those supplied by host biosphere through the blood stream, e.g., oxygen, trace elements, and hormones, and those produced locally, e.g., chemokines and cytokines. The lines connecting cell types suggest possible interactions.

Figure 3

Targeting the prostate cancer metastasis ecosystem for cancer therapy. The ecosystem of prostate cancer bone metastases presents several targets for cancer therapy that are currently being studied in the preclinical and clinical settings. Agents to inhibit osteoclast maturation and function (bisphosphonates) as well as endothelial cell proliferation (bevacizumab) are already in clinical use. Agents that inhibit osteoblast function are in clinical trial. Agents that modulate the cells of the immune system hold promise and are being studied preclinically as well as clinically. The recognition that cancer cells interact with mesenchymal and hematopoietic stem cells has opened new avenues of investigation for the treatment of bone metastases.