The microenvironment can have a very profound effect on the ability of tumor cells to develop into clinically relevant tumors. This was first hypothesized by Stephen Paget who, in his seed and soil theory, theorized that metastatic tumors (seed) will only grow in microenvironments (soil) for which they are suited [
9]. The microenvironment is in direct contact with the tumors cells and thus acts as a critical source of vital signals needed for tumor cell survival and proliferation [
10]; adapting to the microenvironment is an essential step in successful metastatic tumor growth. While some tumors have a predisposition towards metastasizing to specific organs [
2,
11,
12,
13,
14], they may not be able to immediately colonize the new region due to inefficient interactions with the microenvironment [
6]. DTCs may encounter a new environment in which they are not compatible with and therefore cannot fully engage the extracellular matrix. For example, Barkan
et al. showed that cells incapable of making cytoskeletal rearrangements to fully engage the microenvironment will enter into and remain in a dormant state until they can make the needed modifications [
15]. Using breast cancer cell lines D2Al and D2.0R, which exhibit similar proliferation rates
in vitro, have different characteristics
in vivo D2.0R remain as single quiescent cells for extended periods of time, compared to D2A1 cells which remain dormant for a relatively short time and switch to form rapid growing masses, Barkan
et al. showed that these cells differentiate in their ability to express fibronectin and therefore induce β-1 integrin signaling and cytoskeletal rearrangements [
15]. Under these conditions, the microenvironment is interpreted as hostile, as the cells only have transient adhesion to the microenvironment, leading to the activation of stress response signaling such as, urokinase
-type plasminogen activator receptor (uPAR) deactivation [
15,
16,
17]. uPAR is a metastasis-associated receptor that leads to tumor growth through α5β1 integrin interactions [
16]. Low uPAR signaling prevent DTCs from interacting with and activating B1 integrin and downstream signaling events, including cytoskeletal dynamics, reducing microenvironmental interactions [
6,
15,
18]. In addition to down regulation of uPAR signaling, microenvironment-induced stress also leads to p38 activation and ERK1/2 deactivation [
19,
20,
21]. p38 activation has been shown to inhibit tumor progression as it implicated in promoting growth arrest, by activating p53 andp16 signaling, and down regulating cyclin D1 [
22,
23,
24,
25]. It has also been implicated in reducing the expression and activation of mitogenic signaling of ERK1/2 [
19]. The ratio of ERK1/2 and p38, activation has been shown to predict if a tumor cell will proliferate or enter a dormant state upon dissemination, with a high ratio suggesting proliferation and a low ratio suggesting dormancy [
20].
Microenvironment induced stress may induce the expression or activation of metastasis suppressor genes (MSGs) [
26]. MSGs are genes that prevent the formation of metastases, while having little to no effect on primary tumor formation. MSGs act on a wide range of cellular processes to inhibit metastatic growth including activation of signaling pathways which promote dormancy through cell cycle arrest or deactivating signaling pathways which promote cell proliferation (reviewed in [
27]). The MSGs mitogen-activated proteins kinase-kinase (MKK) 4 and MKK6 have been shown to activate p38 signaling [
28,
29]; with MKK4 also activating and the cyclin-dependent kinase inhibitor p21, inducing cell cycle arrest. MSG N-myc downstream-regulated gene 1 (NDRG1), has been implicated in regulating oncogenic signaling pathways of TGF-β, PI3K, and Ras [
30].
In addition to activating stress responses through inefficient adhesion/interaction, there are reports that suggest that microenvironments, as part of their normal activity, can secrete factors that are anti-proliferative to DTCs. For example bone marrow stromal cells secrete bone morphogenic protein 7 (BMP7), which has been shown to induce dormancy in prostate cancer tumor cells [
31]. The secretion of BMP7 leads to the increase of the metastasis suppressor gene NDGR1, which subsequently leads to an increase in p38 activation, cell cycle inhibitor p21 expression and ultimately cell cycle arrest [
31]. Another example, also within the bone, occurs with the secretion of growth arrest-specific 6 (GAS6) by osteoblasts and tumor cells, which induces prostate cancer tumor cell dormancy [
32]. Shiozawa
et al. showed that GAS6 expression within the bone leads to a decrease in prostate cancer cell proliferation and an increase in chemoresistance [
32]. Lim
et al. showed that breast cancer cells in contact with bone stromal cells enter G0/G1 arrest by receiving proliferation-inhibiting microRNAs from the stromal cells, a phenomenon that is inhibited when gap junction intercellular communication is inhibited [
33].
In addition to stressed induced MSG expression, some cells disseminate from the primary tumor with a gene expression profile that is prone to tumor dormancy. Recent studies have found gene expression signatures within primary tumors (in addition to ERK1/2 and p38 ratio) that predict if tumors will produce dormant cells with early or late reoccurrence [
34,
35]. Kim
et al. using gene signatures identified in dormancy models of tumor cell quiescence and angiogenic failure, generated a 49-gene expression profile [
34]. Using this gene profile, they have developed a scoring system to determine if tumor will produce late or early reoccurring tumors.