Trks And The Regulation Of Cancer Growth

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The regulation of cell number during development or in cancer growth reflects a balance of signals that promote proliferation or differentiation and survival or apoptosis. Neurotrophin activation of Trks helps to determine this balance during development and oncogenesis. Thus in cancer Trks can be helpful or hurtful biological modifiers and positive or negative prognostic indicators. Trk activities have been described in diverse cancers arising from many tissues including medullary thyroid carcinoma (McGregor et al., 1999), Wilms' tumor (Donovan et al., 1994; Eggert et al., 2001), glioblastoma multiforme (Singer et al., 1999), lung cancer (Ricci et al., 2001), pancreatic cancer (Schneider et al., 2001), melanoma (Innominato et al., 2001), leukemia (Eguchi et al., 1999), breast cancer (Descamps et al., 1998) and Ewing's sarcoma (Nogueira et al., 1997) (Table 1). A review of well described Trk activities in prostate cancer, medulloblastoma and neuroblastoma serves to demonstrate the range of effects Trks can have in cancer.

3.1 Prostate Cancer-Survival

Androgen-sensitive prostate cancer is a treatable disease because the cancer cells depend upon an androgen source for survival (Kyprianou et al., 1990). Androgen ablation and removal of the survival signal results in widespread apoptosis. Lethal, metastatic, prostate cancer is characterized by a dependence upon androgens and other factors for cancer cell survival. Androgen ablation results in the apoptosis of only the subset of cells that are androgen-dependent. The remainder of the cells, continue to survive through the actions of other survival factors. NGF acting through TrkA appears to be a critical survival factor for androgen- independent prostate cancer.

Normal prostate epithelium expresses TrkA, but neither TrkB nor TrkC. Normal prostatic stroma expresses NGF (Dalal and Djakiew, 1997; Guate et al., 1999; Pflug et al., 1995) establishing a paracrine relationship between normal stroma and epithelium. Acquisition of an abnormal autocrine Trk survival pathway is common in malignant prostate carcinoma: 60-70% of primary prostate cancers express TrkA, often at elevated levels. In addition, 60-70% of primary prostate cancers also exhibit abnormal expression of TrkB or TrkC. Increased TrkA and C expression is positively correlated with increasingly abnormal patterns of growth (Dionne et al., 1998; Guate et al., 1999). Consequently, as many as 80% of metastatic lesions express one or more Trks. These same malignant prostate cancers also synthesize and secrete neurotrophins that stimulate Trk signaling and downstream survival in an autocrine/paracrine fashion (Weeraratna et al., 2000).

In the normal prostate the role of NGF is unclear. Pharmacological inhibition of TrkA signaling in normal prostate has no effect on TrkA expressing prostate cells (Dionne et al., 1998). Thus while TrkA may mediate a survival signal in normal prostate, survival is not exclusively dependent upon this activity. In contrast, malignant prostate cancer can exhibit exclusive dependence on the Trk survival signal. In several studies utilizing different pharmacological agents, inhibition of Trk kinase activity and all downstream signaling resulted in dramatic growth inhibition and apoptosis of prostate cancer in vitro and in xenograft models of disease (Delsite and Djakiew, 1996; Dionne et al., 1998; George et al., 1999; Weeraratna et al., 2001). Thus prostate cancer, through the acquisition of an autocrine/paracrine neurotrophin survival signal develops a survival advantage. Clinical experience in treating androgen-independent prostate cancer suggests that this renders it relatively resistant to apoptosis inducing agents such as chemotherapy.

3.2 Medulloblastoma-Apoptosis

Neurotrophins are best known for their role in the development and functioning of the nervous system. Among the model systems that have helped illuminate the diverse functions of neurotrophins is the cerebellum. Here neurotrophins are known to regulate differentiation, apoptosis and migration of neuronal precursor cells and modulate synaptogenesis and synaptic functioning. Some of these roles ate recapitulated in a tumor of cerebellar granule cells, medulloblastoma (Eberhart et al., 2001). The role of Trks in medulloblastoma first became apparent when a clear correlation between increased levels of TrkC expression and patient survival was established (Segal et al., 1994). In addition to TrkC, some medulloblastoma tumors also express TrkA and TrkB as well as NGF, BDNF and NT3 (Tajima et al., 1998). Anatomical co-localization of neurotrophin ligands and receptors does occur and suggests that autocrine/paracrine loops can exist in the case of BDNF/TrkB and NT3/TRkC (Tajima et al., 1998; Washiyama et al., 1996).

All medulloblastomas appear to express TrkC but only those with high levels of expression possess favorable biological behavior (Grotzer et al., 2000; Pomeroy et al., 2002; Segal et al., 1994). This appears to be the result of the TrkC transduction of differentiation and pro-apoptotic NTS signals (Kim et al., 1999). In addition the co-localization of NT3 and TrkC with markers of differentiation such as neurofilament suggest that NT3 may induce neuronal differentiation of medulloblastoma (Tajima et al., 1998).

Table 1. TRK activation in human cancer.

Diagnosis

Neurotrophin Expression

Trk Expression

Oncogenic Fusion Proteins

Papillary Thyroid Ca Infantile Fibrosarcoma AML

Trk Receptors

Prostate Cancer Mcdullobl astoma Neuroblastoma

Malignant Melanoma Pancreatic Cancer Medullary Thyroid Ca Wilms' Tumor

NGF and/or BDNF and/or NT3 NGF and/or BDNF and/or NT3 BDNF

NGF and/or BDNF and/or NT3 BDNF and/or NT3

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