In 1889, Paget suggested in what has become known as soil-and-seed hypothesis that a cancer cell thrives wherever it encounters a permissive environment, thus explaining the preferred sites of metastasis . While the ensuing research has focused mainly on the seed, i.e., the mutated cancer cell, emerging evidence suggests that the soil, i.e., the microenvironment, far from being a randomly encountered niche during metastasis, is, already at the site of the primary tumor, a specialized tissue that should be viewed as an integral part of the tumor . While the general focus when dealing with the TME lies on the tumor-associated stroma cells, it is composed of not only cells, such as fibroblasts, epithelial and endothelial cells, macrophages, and leukocytes, but also components of the extracellular matrix, such as collagen and fibronectin . Mutated cells communicate with these components via heterotypic cell-cell interaction, in the case of other cells, or via cell-substrate interaction, when dealing with components of the extracellular matrix . These interactions are not only essential for the three-dimensional organization of the tumor, including but by no means limited to vascularization, they also mediate a phenomenon called AMAR, or adhesion-mediated apoptosis resistance : cancer cells which are in contact with their microenvironment show increased resistance towards both radio- and chemotherapy, which induce apoptosis, a form of cell suicide. This is mediated by enhanced survival signaling or a reduction of the death signaling and, importantly, specifically blocking these interactions can in turn sensitize the mutated cells for apoptosis, even if the cell and its TME are not physically removed from each other . Therefore, inhibiting the interaction between mutated cell and TME, in essence, blinding the cancer cell to its surroundings, leads to a reduction in therapeutic intervention needed, thus lowering the risks of long-term side effects. Furthermore, increased isolation from the cancer niche might even lead to anoikic cell death, the cancer cells dying without the need of additional therapeutic intervention . It has even been suggested that the development of the TME occurs concurrently and is essential for the multistep carcinogenesis  and there is compelling evidence for the formation of a premetastatic niche prior to the establishment of a colony of mutated cancer cells, i.e., the soil is fertilized prior to the seed growth . Therapeutically, reestablishing the `normal' unaltered microenvironment can be sufficient to block tumor progression and tumor formation ,. In addition, far from being a hindrance during local invasion and metastasis, which needs to be broken down in order for the cancer cell to progress to distant sites, several components of the TME actively cooperate with tumor cells in these processes . Our own recent work suggests that by inhibiting the interaction between cancer cell and TME - in particular, Fibronectin, which was predominately produced by those cells at the leading invasive edge of the tumor, inhibits their migratory capacity - metastasis can be blocked (summarized in ). However, depending on the target, the opposite can occur, blocking desmosomes, tethering point for intermediate filaments, or tight junctions, at the boundary between apical and basal domains of the plasma membrane, within the tumor can actually increase invasion .
The complexity of the TME's role has been further highlighted in recent research into the role of macrophages within the tumor. These cells, which are phagocytes involved in both innate and adaptive immunity, make up a rather mobile component of the TME. They are attracted to hypoxic and necrotic areas of the tumor and are believed to mediate chronic inflammation, apoptosis resistance, and neovascularization, i.e., to ensure tumor survival and propagation. Tumor-associated macrophages (TAMs) can often not penetrate the tumor growth due to the altered metabolism of the cancer cell, which, in essence, creates a too toxic environment for TAMs to thrive . Basically, the same signals which attract TAMs to the tumor prevent them from reaching the majority of cancer cells. This seems rather counter-intuitive if TAMs are recruited to the tumor to facilitate oxygen supply and, thus, metabolic alterations and survival of the tumor. However, if one considers the role of macrophages in the body's immune response, a rather intriguing possibility emerges: while the TAMs can be co-opted by the cancer cells at the tumor periphery to mediate invasion, they need to be kept out of the actual growth, as they might exert an anti-tumorigenic effect there. Several new studies seem to confirm that, both a healthy bacterial flora to activate the immune system and macro-phages to execute the immune response are needed for chemotherapeutic intervention to be fully successful -. Interestingly, therapeutically altering the TME to enhance the macrophage response also seems practical in non-solid cancers, such as leukemia .
A frequently voiced objection to targeting the TME is that it provides a far less comfortable therapeutic window, i.e., the view that non-mutated cells within a cancer are patient cells and therefore targeting those cells will lead to increased damage of healthy tissue. While correct on a strictly genetic level, this caveat does not take into account the dynamic reciprocity that exists between the different components of the tumor. In essence, not only does the TME provide the mutated cell with a niche in which to survive, but the cancer cell also alters the TME, giving it a distinct phenotype and individual epigenetic signature ,. Importantly, unlike mutated cancer cells, cells from TME readily revert to their non-disease associated phenotype, while providing a slower proliferating, genetically more stable target for therapeutic interventions compared to cancer cells . Therefore, blocking the influence of the cancer cells on the TME and of the TME on the cancer cells, in essence, either targeting the soil or the seed's ability to interact with it, should lead to a more localized disease and can be sufficient to kill cancer cells, either by needing a much reduced amount of additional therapy or without the need of any further radio- or chemotherapy.