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Pictures from Figures 1A and 1B;2A,2B and 2C;6A and 6D;7B Dataset from Figures2-7with data analysis(including Wound Healing assay, Transwell migration and invasion assay) on MCF7, MDA and H2122 AS cell lines

In order to effectively manage and cure cancer we should move beyond the general view of cancer as a random process of genetic alterations leading to uncontrolled cell proliferation or simply a predictable evolutionary process involving selection for traits that increase cell fitness. In our view, cancer is a systemic disease that involves multiple interactions not only among cells within tumors or between tumors and surrounding tissues but also with the entire organism and its internal “milieu”. We define the internal body climate as an emergent property resulting from spatial and temporal interactions among internal components themselves and with the external environment. The body climate itself can either prevent, promote or support cancer initiation and progression (top-down effect; i.e., body climate-induced effects on cancer), as well as be perturbed by cancer (bottom-up effect; i.e., cancer-induced body climate changes) to further favor cancer progression and spread. This positive feedback loop can move the system towards a “cancerized” organism and ultimately results in its demise. In our view, cancer not only affects the entire system; it is a reflection of an imbalance of the entire system. This model provides an integrated framework to study all aspects of cancer as a systemic disease, and also highlights unexplored links that can be altered to both prevent body climate changes that favor cancer initiation, progression and dissemination as well as manipulate or restore the body internal climate to hinder the success of cancer inception, progression and metastasis or improve therapy outcomes. To do so, we need to (i) identify cancer-relevant factors that affect specific climate components, (ii) develop ‘body climate biomarkers’, (iii) define ‘body climate scores’, and (iv) develop strategies to prevent climate changes, stop or slow the changes, or even revert the changes (climate restoration).

Intratumour heterogeneity is often associated with poor response to treatment and bad prognosis. In addition to constitutive genetic/epigenetic sources, phenotypic and functional heterogeneity can reflect cell plasticity due to changes in gene expression patterns induced by signals from the tumour microenvironment or other cells. Positive interactions between cancer clones can increase their fitness and contribute to tumour growth, resistance to drugs and metastasis. Consequently, understanding the pathways involved in such behaviours is of great significance for cancer treatment. To explore if and how genetically distant clones can synergistically enhance each other's metastatic potential, this study used three (two breast and one lung) cancer cell lines with different aggressiveness levels. We found that (i) the conditioned media from the breast and lung aggressive lines induce mesenchymal features and increase the migration and invasion potential of the poorly metastatic breast line, and (ii) in both cases, this interclonal communication is based on the same soluble factor – namely, the tumour growth factor TGF-β1. Furthermore, when the two breast lines are mixed and co-cultured, the invasive potential of both lines is enhanced, and this outcome is dependent on the recruitment of the less aggressive clone into expressing a malignant phenotype. Based on our findings, we propose a two-tier model whereby highly metastatic clones can recruit weakly metastatic clones into acquiring an invasive phenotype, which in turn augments the invasion ability of the former (i.e., a “help me help you” strategy) through shared proteases and/or ECM remodelling. We suggest that such synergistic cooperation can easily emerge via cross-talk involving metastatic clones able to constitutively secrete signalling molecules that induce and maintain their own malignant state (i.e., autocrine/cell-autonomous signalling) and clones that have the ability to respond to those signals (i.e., paracrine/non-cell-autonomous signalling) and express a metastatic phenotype. Taking into account the lack of therapies to directly affect the metastatic process, interfering with such cooperative behaviours that tumour cells engage in during the early steps in the metastatic cascade could provide an additional strategy to increase patient survival.

Intratumour heterogeneity is often associated with poor response to treatment and bad prognosis. In addition to genetic and epigenetic sources, phenotypic heterogeneity can also reflect plastic responses to signals from other cells. The latter can be mediated by various cell-cell interactions, from antagonistic (i.e., competition) to commensalistic or cooperative (mutually beneficial or altruistic). Positive exchanges can increase the fitness of clones and contribute to tumour growth, resistance to drugs and metastasis. Consequently, understanding the pathways involved in such interactions is of great significance for cancer treatment. This study used two breast cancer cell lines with different aggressiveness levels and very different secretome profiles (i.e., MDA-MB-231 and MCF7) to address the nature and mechanistic basis of interclonal crosstalk through paracrine signalling involving soluble factors during the early stages of metastasis. Our data show that MDA-MB-231 is able to recruit MCF7, through TGFβ1-mediated paracrine signalling, into expressing mesenchymal features and increased migration. On the other hand, MCF7 has no effect on the migration of MDA, suggesting a passive/commensalistic interaction. However, we found that the invasive potentials of both lines are enhanced when they are co-cultured, indicating that the two lines act synergistically and that such interclonal interactions can be mutually beneficial in vivo. Taking into account the negative impact that metastasis has on cancer prognosis and the lack of therapies to directly affect this process, interfering with the specific cooperative behaviours that tumour cells engage in during tumour progression should provide an additional strategy to increase patient survival.