Recurrence of cancer in the form of metastatic disease accounts for more than 90% of cancer patient deaths; however, tumor metastasis is considered an inefficient process and disseminated tumor cells can remain indolent for long periods of time. Remarkably little is known about the mechanisms by which otherwise dormant tumors become life-threatening cancers. Our prior work lead to the discovery that certain indolent tumor cells can respond to systemic cues to become overt tumors. These systemic cues were generated by aggressively growing tumors located at distant anatomical sites. Thus, we found that human breast carcinomas (termed “Instigators”) facilitate growth of otherwise-indolent tumor cells and micrometastases (termed “Responders”) located in different anatomical sites. We termed this action-at-a-distance “Systemic Instigation”. Our research is focused on identifying factors that mediate the systemic instigation process and finding ways to interdict their function.

Building a molecular framework of the systemic instigation cascade. We discovered that the circulating cytokine, osteopontin (OPN), is necessary but not sufficient for systemic instigation. The relevance of OPN expression to human cancer pathogenesis has been revealed by studies showing that cancer patients with metastatic disease have elevated blood levels of OPN, which is correlated with reduced survival. We found that instigating tumors secrete OPN in an endocrine fashion to perturb cells in the bone marrow. These bone marrow cells are subsequently mobilized into the circulation and recruited to sites where indolent tumors reside, ultimately stimulating tumor growth. Our observation that OPN is not sufficient to facilitate indolent tumor growth suggests that other factors play a role in systemic instigation. We plan to take various experimental approaches to identify such factors in order to build a molecular framework of the systemic instigation process.

Understanding the role of bone marrow derived cells. Systemic instigation is accompanied by the incorporation of bone marrow derived cells into the microenvironment where responding tumors reside. We found that bone marrow cells of hosts bearing instigating tumors are functionally activated prior to their mobilization; hence, when co-injected with responder cells, these activated bone marrow cells mimic the systemic effects imparted by instigating tumors. Our experimental model system provides us with an opportunity to specifically identify and target bone marrow cell type(s) that are activated in response to instigating tumors. Together with our colleagues in the Hematology Division, we are focusing our research efforts on these bone marrow cell type(s) and how they are affected by endocrine factors released into the circulation by instigating tumors.

Uncovering the initiation of stromal desmoplasia. Perhaps the most surprising aspects of the instigation process came from our observations of the histopathology of the resulting tumors. We observed that responding tumors formed with a reactive stroma – a condition that is associated with poor prognosis for cancer patients – only when growing in the presence of a distant instigating tumor. Our results revealed that the formation of this reactive stroma is governed to some extent on a systemic level by endocrine factors released by certain instigating tumors. Currently, very little is known about the processes that mediate desmoplastic tumor growth; therefore, we hope to dissect the systemic signals that are responsible for this phenomenon.