Douglas Hanahan, Robert A. Weinberg. Hallmarks of cancer: the next generation. Cell, Volume 144, Issue 5, p646–674, 4 March 2011
Depictions of the intracellular circuitry governing cancer cell biology (e.g., Figure 2) will need to be complemented by similar diagrams charting the complex interactions between the neoplastic and stromal cells within a tumor and the dynamic extracellular matrix that they collectively erect and remodel. A reasonably complete, graphic depiction of the network of microenvironmental signaling interactions is still far beyond our reach, as the great majority of signaling molecules and pathways remain to be identified. We provide instead a hint of such interactions in Figure 5, upper. These few well-established examples are intended to exemplify a signaling network of remarkable complexity that is of critical importance to tumor pathogenesis.
Another dimension of complexity is not represented in this simple schematic: both neoplastic cells and the stromal cells around them change progressively during the multistep transformation of normal tissues into high-grade malignancies. This histopathological progression must reflect underlying changes in heterotypic signaling between tumor parenchyma and stroma.
Such stepwise progression is likely to depend on back-and-forth reciprocal interactions between the neoplastic cells and the supporting stromal cells, as depicted in Figure 5, lower. Thus, incipient neoplasias begin the interplay by recruiting and activating stromal cell types that assemble into an initial preneoplastic stroma, which in turn responds reciprocally by enhancing the neoplastic phenotypes of the nearby cancer cells. The cancer cells, which may further evolve genetically, again feed signals back to the stroma, continuing the reprogramming of normal stromal cells to serve the budding neoplasm; ultimately signals originating in the tumor stroma enable cancer cells to invade normal adjacent tissues and disseminate.
This model of reciprocal heterotypic signaling must be extended to encompass the final stage of multistep tumor progression—metastasis (Figure 5, lower right). The circulating cancer cells that are released from primary tumors leave a microenvironment created by the supportive stroma of such tumors. However, upon landing in a distant organ, these cancer cells encounter a naive, fully normal, tissue microenvironment. Consequently, many of the heterotypic signals that shaped their phenotype while they resided within primary tumors may be absent in sites of dissemination, constituting a barrier to growth of the seeded cancer cells. Thus, the succession of reciprocal cancer cell to stromal cell interactions that defined multistep progression in the primary tumor now must be repeated anew in distant tissues as disseminated cancer cells proceed to colonize their newfound organ sites.
Although this logic applies in some cases of metastasis, in others, as mentioned earlier, certain tissue microenvironments may, for various reasons, already be supportive of freshly seeded cancer cells; such permissive sites have been referred to as «metastatic niches». Implicit in this term is the notion that cancer cells seeded in such sites may not need to begin by inducing a supportive stroma because it already preexists, at least in part. Such permissivity may be intrinsic to the tissue site or preinduced by circulating factors released by the primary tumor. The most well-documented components of induced premetastatic niches are tumor-promoting inflammatory cells, although other cell types and the ECM may well prove to play important roles in different metastatic contexts.
The likelihood that signaling interactions between cancer cells and their supporting stroma evolve during the course of multistage tumor development clearly complicates the goal of fully elucidating the mechanisms of cancer pathogenesis. For example, this reality poses challenges to systems biologists seeking to chart the crucial regulatory networks than orchestrate malignant progression. Moreover, it seems likely that understanding these dynamic variations will become crucial to the development of novel therapies designed to successfully target both primary and metastatic tumors.