Perineural invasion in prostate biopsy specimens is associated with increased bone metastasis in prostate cancer

Çiftçi, Seyfettin; Yılmaz, Hasan; Çıftçı, Ercüment; Şimşek, Emrah; Üstüner, Murat; Yavuz, Ufuk; Müezzínoğlu, Bahar; Dillioğlugil, Özdal

doi:10.1002/pros.23067

Cited by 27 publications

(28 citation statements)

References 35 publications

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“…This type of developmental plasticity that increases invasiveness and generates neural- and even bone-like phenotypes might facilitate metastatic dissemination of PCa. Perineural invasion at the primary site is a harbinger of metastatic disease and the neural-type plasticity that we observed could facilitate the interaction of PCa cells with nerves [42, 43]. Furthermore, with evidence that PCa cells use neural networks to metastasize to bone, the neural and bone mimicry generated in our in vitro system suggests that this plasticity may foster dissemination through nerves and establishment in bone [44–46].…”

Section: Discussionmentioning

confidence: 89%

Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance

et al. 2017

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Treatment-induced neuroendocrine transdifferentiation (NEtD) complicates therapies for metastatic prostate cancer (PCa). Based on evidence that PCa cells can transdifferentiate to other neuroectodermally-derived cell lineages in vitro, we proposed that NEtD requires first an intermediary reprogramming to metastable cancer stem-like cells (CSCs) of a neural class and we demonstrate that several different AR+/PSA+ PCa cell lines were efficiently reprogrammed to, maintained and propagated as CSCs by growth in androgen-free neural/neural crest (N/NC) stem medium. Such reprogrammed cells lost features of prostate differentiation; gained features of N/NC stem cells and tumor-initiating potential; were resistant to androgen signaling inhibition; and acquired an invasive phenotype in vitro and in vivo. When placed back into serum-containing mediums, reprogrammed cells could be re-differentiated to N-/NC-derived cell lineages or return back to an AR+ prostate-like state. Once returned, the AR+ cells were resistant to androgen signaling inhibition. Acute androgen deprivation or anti-androgen treatment in serum-containing medium led to the transient appearance of a sub-population of cells with similar characteristics. Finally, a 132 gene signature derived from reprogrammed PCa cell lines distinguished tumors from PCa patients with adverse outcomes. This model may explain neural manifestations of PCa associated with lethal disease. The metastable nature of the reprogrammed stem-like PCa cells suggests that cycles of PCa cell reprogramming followed by re-differentiation may support disease progression and therapeutic resistance. The ability of a gene signature from reprogrammed PCa cells to identify tumors from patients with metastasis or PCa-specific mortality implies that developmental reprogramming is linked to aggressive tumor behaviors.

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Section: Discussionmentioning

confidence: 89%

Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance

et al. 2017

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“…Thus, nerve dispersal selects for mobile cells that can survive the nerve fiber environment and locomote along the corridor. Thus, the adaptive mobile foraging phenotype is selected for in an ideal metastatic “seed” and is evidenced by the positive association of perineural invasion and development of bone metastasis (28). …”

Section: Dispersal Corridors Are Barriers To Disseminationmentioning

confidence: 99%

“…Cells dispersing in the lymph pass through lymph nodes before draining into the blood. Some dispersing prostate cancer cells in the lymph will be trapped in and colonize the lymph node (28,69), resulting in regional lymph node metastasis.…”

Section: Dispersal Corridors Are Barriers To Disseminationmentioning

confidence: 99%

Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis

Groot

Roy

Brown

et al. 2017

Molecular Cancer Research

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Metastasis is the consequence of a cancer cell that disperses from the primary tumor, travels throughout the body, and invades and colonizes a distant site. Based on Paget’s 1889 hypothesis, the majority of modern metastasis research focuses on the properties of the metastatic “seed and soil,” but the implications of the primary tumor “soil” have been largely neglected. The rare lethal metastatic “seed” arises as a result of the selective pressures in the primary tumor. Optimal foraging theory describes how cancer cells adopt a mobile foraging strategy to balance predation risk and resource reward. Further selection in the dispersal corridors leading out of the primary tumor enhances the adaptive profile of the potentially metastatic cell. This review focuses on the selective pressures of the primary tumor “soil” that generate lethal metastatic “seeds” which is essential to understanding this critical component of prostate cancer metastasis. Implications Elucidating the selective pressures of the primary tumor “soil” that generate lethal metastatic “seeds” is essential to understand how and why metastasis occurs in prostate cancer.

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“…Therefore, it has been hypothesized that nerve components within the marrow contributes to bone metastatic progression [79]. Interestingly, prostate cancer cells have a high affinity to nerve fibers [80,81], and perineural invasion in the primary tumor has been proposed as a predictor for prostate cancer bone metastasis [82,83]. These findings suggest that the crosstalk between prostate cancer and the central nervous system might be in part responsible for the bone metastatic process.…”

Section: Mechanisms Of Prostate Cancer Bone Metastasismentioning

confidence: 99%

Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis

2017

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Bone is the most common site of prostate cancer metastasis. Once prostate cancer cells metastasize to bone, the mortality rate of prostate cancer patients increases significantly. Furthermore, bone metastases produce multiple skeletal complications, including bone pain that impairs the patients' quality of life. Effective therapies for bone metastatic disease are underdeveloped with most current therapies being primarily palliative with modest survival benefit. Although the exact mechanisms through which prostate cancer metastasizes to bone are unclear, growing evidence suggests that the bone marrow microenvironment, particularly its hematopoietic activity, is a significant mediator of prostate cancer bone tropism. Moreover, the bone microenvironment may regulate metastatic prostate cancer cells between dormant and proliferative states. In this review, we discuss (1) how prostate cancer cells interact with the bone microenvironment to establish bone metastases and (2) current and future potential treatments for prostate cancer patients with bone metastases.

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Perineural invasion in prostate biopsy specimens is associated with increased bone metastasis in prostate cancer

Abstract: PNI in the TRUS-Bx specimens is the most powerful predictive histopathological feature for bone metastasis, by increasing the risk of bone metastasis 11-fold in NCCN bone scan indicated patients (Group 2).

Cited by 27 publications

References 35 publications

Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance

Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance

Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis

Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis

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