Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment

Abstract

Pleiotrophin (PTN,Ptnangiogenesis ͉ collagen ͉ polyoma virus middle T ͉ scirrhous carcinoma ͉ stromal fibroblasts B reast cancers progress through stages of increasing malignancy triggered by genetic and epigenetic mutations that promote their growth, invasiveness, and metastasis. Because mortality from breast cancer is most often due to growth of distant metastases that are not controlled by existing therapies, there is a vital need to better understand the molecular pathogenesis of breast cancer and to identify mutations in breast cancer cells that promote breast cancer progression and lead to metastasis (1).Pleiotrophin [PTN (the protein), Ptn (the gene)] is a 136-aa heparin-binding cytokine (2, 3) frequently detected in human breast cancers (4). Its expression is constitutive in human breast cancer cells in which it has been tested (5). Furthermore, PTN stimulates functional responses that are known to stimulate breast cancer progression, such as proliferation (2, 3), cytoskeletal rearrangements, and loss of cell-cell adhesion (6, 7), transformation (8), induction of an epithelial to mesenchymal transition (6), and stimulation of tumor angiogenesis (9, 10), in cultured cells or in cells that ectopically express Ptn. These functional responses to PTN are likely to be significant in progression of breast cancers, because interruption of constitutive PTN signaling in human breast cancer cells that inappropriately express Ptn reverses their transformed phenotype in vitro and in vivo (5); these PTN-stimulated functional responses thus support the possibility that mutations in breast cancer cells, which deregulate endogenous Ptn expression, may initiate similar functional responses and lead to breast cancer progression.In the following studies, three models were tested to determine whether inappropriate expression of Ptn alone is sufficient to induce breast cancer or whether inappropriate expression of Ptn cooperates with different pathogenic mechanisms that stimulate breast cancer progression. Together, the studies demonstrate both in vivo and in vitro that inappropriate expression of Ptn promotes breast cancer progression; the studies also demonstrate that PTN secretion from human breast cancer cells alone is sufficient to promote progression of breast cancer to a more aggressive breast cancer phenotype through activation of stromal cells and extensive remodeling of the microenvironment. Results Mouse Mammary Tumor Virus (MMTV)-Ptn Fails to Induce BreastCancer in MMTV-Ptn Transgenic Mice. To test whether inappropriate expression of Ptn alone is sufficient to induce breast cancers in mice, MMTV-long terminal repeat-driven-Ptn (MMTV-Ptn) transgenic mice were generated [see supporting information (SI) Materials and Methods and SI Fig. 5]. Female MMTV-Ptn mice had normal mammary gland development and lactation and developed pups in normal numbers and in size equal to that of control mouse pups. Expression of the MMTV-Ptn transgene was detected in high levels in breast epithelial cells. In extensive microscopic exami...

The Pro-angiogenic Cytokine Pleiotrophin Potentiates Cardiomyocyte Apoptosis through Inhibition of Endogenous AKT/PKB Activity

“…In fact, PTN has been associated with tissue repair and remodeling. In cerebral ischemia, for example, PTN is strongly up-regulated in developing microvasculature, endothelial cells, and macrophages (14), and its secretion stimulates breast cancer progression through remodeling of the tumor microenvironment (40). Because heart failure is also associated with significant remodeling, our data suggest that the effects of PTN are not limited to revascularization.…”

Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis

“…Many tumor cell lines and different types of freshly derived tumors including MM, choriocarcinoma, and breast, pancreatic, colon, ovarian, and prostate cancers highly express PTN. [16][17][18][19]21 Recent studies have also shown the important role of PTN in new blood vessel development 13,16,59,60 and in PTN-stimulated tumor angiogenesis. 17,20 PTN is also a factor important in many other functions required for the growth and maintenance of cancers including proliferation, survival, invasion, and metastasis of tumor cells as well as remodeling of the tumor microenvironment.…”

“…[16][17][18][19]21 Recent studies have also shown the important role of PTN in new blood vessel development 13,16,59,60 and in PTN-stimulated tumor angiogenesis. 17,20 PTN is also a factor important in many other functions required for the growth and maintenance of cancers including proliferation, survival, invasion, and metastasis of tumor cells as well as remodeling of the tumor microenvironment. 17,21,61 This protein has been recently shown to be regulated by tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and deletion of PTEN increases PTN gene transcription and tumorigenicity in mouse models.…”

“…14,15 PTN is up-regulated at sites of wound healing and blood vessel formation, 12 and stimulates creation of vessels when injected into injured tissues. 13 Many different solid tumors express this protein, [16][17][18][19] and its secretion from tumor cells stimulates new blood vessel formation. 17,20 We have recently demonstrated that PTN is expressed and secreted by the malignant plasma cells from MM patients.…”

“…13 Many different solid tumors express this protein, [16][17][18][19] and its secretion from tumor cells stimulates new blood vessel formation. 17,20 We have recently demonstrated that PTN is expressed and secreted by the malignant plasma cells from MM patients. 21,22 Serum levels of PTN are elevated in cancer patients including MM, and the amount of this protein correlates with the patient's disease status and response to treatment.…”