Molecular basis of metastasis - PubMed (original) (raw)

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Molecular basis of metastasis

Anne C Chiang et al. N Engl J Med. 2008.

Abstract

Metastasis is the end product of an evolutionary process in which diverse interactions between cancer cells and their microenvironment yield alterations that allow these cells to transcend their programmed behavior. Tumor cells thus populate and flourish in new tissue habitats and, ultimately, cause organ dysfunction and death. Understanding the many molecular players and processes involved in metastasis could lead to effective, targeted approaches to prevent and treat cancer metastasis.

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Conflict of interest statement

No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1

Figure 1. Tumor Initiation and Metastasis

The initiation and progression of tumors depend on the acquisition of specific functions by cancer cells at both the primary and metastatic sites. Functions associated with tumor initiation are provided by oncogenic mutations and inactivation of tumor-suppressor genes. Functions associated with the initiation of metastasis include functions to which tumor cells resort for local invasion and for circumventing hypoxia and other limitations facing a growing tumor. Most functions for the initiation of both the tumor and metastasis remain essential for cancer cells to continue their metastatic development. Functions for metastasis progression provide a local advantage in a primary tumor and a distinct and sometimes organ-specific function during metastasis. Cancer cells that are endowed with these three sets of functions still depend on functions associated with metastasis virulence; these functions confer a selective advantage solely during the adaptation and takeover of a specific organ microenvironment. Genes associated with each of these functions have been identified in recent years.

Figure 2

Figure 2. Patterns of Metastatic Spread of Solid Tumors

Brain metastases may occur as a result of hematogenous spread late in the course of a widely metastatic tumor, or as a result of secondary metastasis from a primary or a metastatic tumor that can access the arterial circulation through the pulmonary venous circulation to seed the brain. Tumors with the highest incidence of brain metastases include lung carcinoma, breast carcinoma, melanoma, and to a lesser extent, renal-cell and colorectal carcinomas. Leptomeningeal disease may develop through the spread of cancer cells through perineural lymphatic vessels, and it is a sign of advanced disease. Some tumors have a strong proclivity for dissemination to the lungs; for example, in one study, the rate of dissemination associated with sarcoma was 23%. Other tumors that frequently spread to the lungs include renal-cell, colorectal, melanoma, and breast carcinomas., Gastrointestinal tumors easily access the liver circulation through the portal-vein system. The incidence of liver metastases is highest among patients with colorectal or pancreatic cancer, followed by breast and lung cancers. Estrogen-receptor–negative breast-cancer tumors more often metastasize to visceral organs, including the liver, whereas estrogen-receptor–positive breast cancer more often metastasizes to the bone. Bone metastasis occurs in patients with primary tumors associated with breast, lung, prostate, renal-cell, and colon cancer, in this order of frequency. Bone metastases may be primarily osteolytic or osteoblastic, depending on the tumor of origin.

Figure 3

Figure 3. Genes, Functions, and Cellular Players in Organ-Specific Metastasis

Organ-specific metastasis of breast-cancer cells involves different molecular players during colonization of the lungs and the bones. In the lung, cancer cells producing EREG, COX-2, MMP-1, and ANGPTL4 are better equipped to exit the pulmonary vasculature, since these factors alter the integrity of lung microcapillary endothelia; this function is less important for infiltration into the bone marrow because of the naturally fenestrated structure of the bone marrow sinusoid vasculature. In the lung parenchyma, the activity of the antidifferentiation gene ID1 and interactions with still unknown “niche” factors promote tumor reinitiation. In the bone marrow, stromal-cell–derived factor 1 (SDF-1), acting through its chemokine (C-X-C motif) receptor (CXCR4) on cancer cells, is thought to provide cell-survival functions. The secretion of parathyroid hormone–related peptide (PTHrP), interleukin-6, tumor necrosis factor α (TNF-α), interleukin-11, and other factors by cancer cells stimulates osteoblasts to release the ligand for the receptor activator of nuclear factor-κB (RANKL), which in turn stimulates osteoclast differentiation from myeloid progenitor cells. Other cancer cell–derived factors suppress the production of the RANKL antagonist osteoprotegerin, augmenting the efficacy of RANKL. The lytic action of osteoclasts releases bone matrix–associated growth factors, including transforming growth factor β (TGF-β), insulin-like growth factor I (IGF-I), and bone morphogenetic proteins (BMPs). IGF-I is a survival factor, and TGF-β incites cancer cells to further release PTHrP, interleukin-11, and other prometastatic factors, establishing a vicious cycle.

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