AACR centennial series: the biology of cancer metastasis: historical perspective

Abstract

Metastasis resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His "seed and soil" hypothesis was substantiated a century later with experimental studies, and numerous reports have confirmed these seminal observations. An improved understanding of the metastatic process and the attributes of the cells selected by this process is critical for the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, so metastasis prevention may not be relevant. Treating systemic disease and identifying patients with early disease should be our goal. Revitalized research in the past three decades has focused on new discoveries in the biology of metastasis. Even though our understanding of molecular events that regulate metastasis has improved, the contributions and timing of molecular lesion(s) involved in metastasis pathogenesis remain unclear. Review of the history of pioneering observations and discussion of current controversies should increase understanding of the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and should lead to the design of successful therapy.

Figure 1

The process of cancer metastasis consists of sequential, interlinked, and selective steps with some stochastic elements. The outcome of each step is influenced by the interaction of metastatic cellular subpopulations with homeostatic factors. Each step of the metastatic cascade is potentially rate limiting such that failure of a tumor cell to complete any step effectively impedes that portion of the process. Therefore, the formation of clinically relevant metastases represents the survival and growth of selected subpopulations of cells that preexist in primary tumors.

Figure 2

Tumors can secrete growth factors and cytokines that result in the expansion and mobilization of myeloid progenitors from the marrow with trafficking to various extramedullary sites including the spleen, liver, lungs and primary and metastatic tumor lesions. These committed myeloid progenitors (CMP) can mature into dendritic cells (DCs) myeloid derived suppressor cells (MDSCs) and macrophages including tumor-associated macrophages (TAMs) as well as become activated, or “paralyzed”, within the tumor environment. These heterogeneous cells include progenitor cells, immature cells, mature, and activated cells. Dependent upon the infiltrating subset and extent of maturation and activation, these cells can be a critical component and regulator of angiogenesis, vascularogenesis, and tumor regression or growth.

Figure 3

The clonal selection model of metastasis suggests that the cell populations in the primary tumor with all of the genetic prerequisites required for metastatic capacity are the subpopulations that metastasize. Further, both the cells within the primary tumor and the metastatic lesion(s) can continue to diversify as the lesions grow.

Figure 4

The immune cells infiltrating tumors can regulate their growth, progression, and metastasis. Tumor regression is associated with infiltration by mature dendritic cells (DCs) and cytotoxic T cells (CTL) and type 1 T-helper type 1 bioactivity. Contrasting with this, tumor growth is facilitated via immune mediated immunosuppression and neoangiogenesis following infiltration of tumors with immature DCs, myeloid-derived suppressor cells, (MDSCs) plasmacytoid DCs, (pDCs) M2 macrophages, as well as T regulatory (T-reg) cells and a low frequency of CD4 and CD8 effector T cells.