Clin. Cancer Res., 9: 1639 −1647, 2003

Tumors and Their Microenvironments: Tilling the Soil : Commentary re: A. M. Scott et al., A Phase I Dose-Escalation Study of Sibrotuzumab in Patients with Advanced or Metastatic Fibroblast Activation Protein-positive Cancer. Clin. Cancer Res., 9: 1639 −1647, 2003. Jonathan D. Cheng and Louis M. Weiner Clin Cancer Res 2003;9:1590-1595. Updated Version Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/9/5/1590 Cited Articles This article cites 45 articles, 17 of which you can access for free at: http://clincancerres.aacrjournals.org/content/9/5/1590.full.html#ref-list-1 Citing Articles This article has been cited by 4 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/9/5/1590.full.html#related-urls E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Subscriptions Publications Department at [email protected]. Permissions To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from clincancerres.aacrjournals.org on November 12, 2012 Copyright © 2003 American Association for Cancer Research 1590 Vol. 9, 1590–1595, May 2003 Clinical Cancer Research The Biology Behind Tumors and Their Microenvironments: Tilling the Soil Commentary re: A. M. Scott et al., A Phase I Dose-Escalation Study of Sibrotuzumab in Patients with Advanced or Metastatic Fibroblast Activation Protein-positive Cancer. Clin. Cancer Res., 9: 1639–1647, 2003. Jonathan D. Cheng,1 and Louis M. Weiner “seminal influence” on the metastatic microenvironment, and Fox Chase Cancer Center, Department of Medical Oncology, thereby act together with the distant organ to effect tumor Philadelphia, Pennsylvania 19111 metastases. The identity of these seminal influences is a subject of active investigation but remains elusive. However, The Shifting Paradigm the importance of tumor-associated fibroblasts, the predom- The conventional concept of tumor-host interactions is inant cell in the microenvironment, has become more evident. rooted in the realm of parasitology. A tumor invades an unsus- pecting host, and in response to this assault, the host attempts to Tumor Stromal Fibroblasts: Contracted Farmers resist the advances of the tumor by calling on the armamentar- Both in vivo and in vitro studies have demonstrated that ium of the immune system. This implies a fundamental oppo- fibroblasts contribute to tumor formation and growth rates sition between the tumor and host in purpose and intent. How- (6), and can be thought of as “contracted farmers” used by ever, an accumulation of evidence points to an alternative tumors to prepare the microenvironment. Fibroblasts coin- paradigm, where the tumor microenvironment is not an idle oculated with breast or bladder tumor cell lines in nude mice bystander, but actively participates in tumor progression and shorten tumor latency and increase tumor growth (7). Fibro- metastasis (1, 2). In fact, stromal cells and their cytokines blasts cultured from malignant tumors have stimulatory ef- coordinate critical pathways that exert important roles in the fects on MCF-7 cells, whereas fibroblasts cultured from ability of tumors to invade and metastasize (3). normal tissue are inhibitory (8). Phenotypic differences In this issue, Scott et al. (4) describe a Phase I clinical trial among tumor-associated fibroblasts have also been seen. using the radiolabeled antibody sibrotuzumab to target the tu- Fibroblasts with smooth muscle differentiation, termed myo- mor stromal antigen FAP2 in metastatic lung and colon cancers. fibroblasts, are abundant in the stromal cells of malignant Human FAP is unique in its selective expression by tumor breast tissue but are rarely seen in normal breast tissue (9). stromal fibroblasts in epithelial carcinomas, but not by epithelial These findings suggest that tumor-associated fibroblasts are carcinoma cells, normal fibroblasts, or other normal tissues. functionally distinct compared with fibroblasts that are not in Therefore, FAP is an attractive target for the study of tumor the tumor microenvironment, and subpopulations of fibro- stromal cell biology and provides valuable insights into the roles blast may perform specialized functions to coordinate events of the tumor microenvironment. FAP may exemplify pathways required for tumor invasion and metastasis. Thus, fibroblasts by which the microenvironment soil is “tilled” in preparation for provide critical frameworks for tumor growth and metastasis. tumor invasion and metastasis. The microenvironment can also influence tumorigenic transformation. Kinzler and Vogelstein (10) proposed the The Tumor Microenvironment Soil concept of landscaper defects to explain the increased inci- The process of tumor metastasis was described using the dence of colorectal cancer in patients with juvenile polyposis “seed and soil” analogy by Paget (5) more than 100 years syndrome or ulcerative colitis. In this situation, the prolifer- ago. His landmark paper in 1889 examined 735 patients with ating stromal cells predispose the normal epithelial cells to breast cancer at autopsy and showed that the distribution of undergo malignant transformation. Thus, stromal inflamma- metastases did not occur by chance, but was regulated by the tion and proliferation eventually lead to the development of predisposition of congenial soil. For example, the liver had a malignant epithelial transformation because of an altered 14-fold higher incidence of metastases compared with the microenvironment terrain. Thus, the gene expression pattern spleen, although these organs roughly possess the same cir- of the fibrotic stroma is distinct from that of the carcinoma culatory volume. Paget (5) proposed that tumor cells, or cells. Iacobuzio-Donahue et al. (11, 12) used serial analysis “seeds,” were randomly scattered by vascular routes, but of gene expression techniques in breast cancer to show that could only form metastatic deposits if they landed in conge- five regions of invasive tumors can be identified, each with a nial territory, or “soil.” He hypothesized that tumors have a distinct gene expression profile. These regions consist of the neoplastic epithelium, angioendothelium, inflammatory stroma, panstroma, and juxtatumoral stroma. Furthermore, they identified receptor-ligand pairs between the neoplastic epithelium and the surrounding stroma, implying significant Received 3/25/03; accepted 3/28/03. communication between host and tumor compartments. In 1 To whom requests for reprints should be addressed, at Fox Chase addition, loss of heterozygosity has been identified in the Cancer Center, Department of Medical Oncology, 7701 Burholme Av- enue, Philadelphia, PA 19111. Phone: (215) 728-7083; Fax: (215) 728- fibrotic reaction surrounding pancreas cancer that is distinct 3639; E-mail: [email protected]. from the loss of heterozygosity pattern in pancreas adenocar- 2 The abbreviations used are: FAP, fibroblast activation protein. cinoma (13). A number of these genes identified in the Downloaded from clincancerres.aacrjournals.org on November 12, 2012 Copyright © 2003 American Association for Cancer Research Clinical Cancer Research 1591 stroma had not been associated previously with pancreatic ing wounds, can provide fertile soil for malignant cell “hom- adenocarcinoma. These studies imply that tumor stroma may ing.” Experimental animal models demonstrate that tumor me- contribute independently to tumor development through tastases arise preferentially in healing wounds (25, 26). The mutation-inducing phenotypes. Such considerations chal- incidence of wound recurrences is proportional to the extent of lenge preexisting notions of a passive stroma that is permis- wound trauma, as larger wounds and wounds that are not sur- sive of local tumor growth. gically repaired exhibit greater frequencies of metastasis. This has been confirmed clinically in the occurrences of surgical FAP: A Tractor wound and port site metastases (27, 28). Given the ability of the The current study by Scott et al. (4) demonstrates the wound healing environment to promote tumor cell proliferation ability to safely administer the humanized anti-FAP antibody (29), tumors may subvert normal wound healing machinery to sibrotuzumab to patients with FAP-positive malignancies with activate factors necessary for tumor metastases. Therefore, tu- tumor-specific uptake as seen by biodistribution images. This mor cells may initiate a permissive microenvironment by induc- clinical trial is an extension of the groundbreaking work by ing expression of permeability factors, procoagulants, or che- Garin-Chesa et al. in discovering the unique distribution of FAP motactic and mitogenic factors. on tumor stromal fibroblasts (14), and has been confirmed by Similarly, the fibrotic reaction seen in desmoplasia tends to Welt et al. (15) as a clinical target. FAP, also known as seprase confer a worse prognosis and may represent a histopathologic marker of fertilized soil. Invasive ductal carcinoma of the breast (16), is a Mr 95,000 cell surface glycoprotein expressed tran- siently in healing wounds, and abundantly on reactive stromal with a fibrotic focus has more aggressive clinical characteristics fibroblasts in Ͼ90% of human epithelial carcinomas (breast, than carcinoma without fibrosis (30, 31). The identification of lung, colorectal, and ovary; Ref. 14). Neural

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