CONTROL OF METASTATIC PROGRESSION OF PROSTATE CANCER

  • Lokeshwar, Bal L, (PI)

Project: Research project

Description

More than one fourth of all men diagnosed with prostate cancer die due to
its malignant metastases. Current clinical experience suggests that early
diagnosis and treatment for localized carcinoma is the best course for
controlling its malignant progression. Evidence from studies on animal
models suggests however, that the primary localized tumor itself contains
subpopulations of malignant tumor cells with invasive and metastatic
potential. The isolation of a subpopulation of invasive cells based on
their ability to invade a basement membrane barrier, might prove the
existence of such cells in primary prostatic tumors. Unique or altered
forms of preexisting characteristics, such as the ability to degrade
surrounding extracellular matrix, increased chemotactic motility, and the
expression of certain cell surface antigens that promote cell-cell
adhesion and thereby escape immune surveillance might endow these cells
with invasive and metastatic potential. Judicious combinations of certain
antitumor drugs and radiation might not only improve cytotoxicity on these
subpopulations, but might also ablate the invasive properties of surviving
cells. This study proposes to test these hypotheses. An in vitro invasion
assay using a reconstituted basement membrane will be used to separate
invasive and noninvasive tumor cell subpopulations from primary prostatic
carcinoma specimens. New tumor lines with different degrees of metastatic
potentials will be established in athymic mice by orthotopic injections of
these subpopulations from the primary carcinoma. The cellular basis of the
invasive and metastatic potential of these tumor lines will be
characterized for the secretion of the basement membrane-degrading
proteolytic enzymes (matrix metalloproteinases), inhibitors of matrix
metalloproteinases, and the cell surface expression of a class of
metastasis-associated cell adhesion molecules (CD44 and its variant
isoforms). Novel methods to control primary tumor metastasis will be
attempted by inhibiting the activities of the matrix metalloproteinases
using their natural and synthetic inhibitors, as well as neutralizing
antibodies. The cytotoxic and anti-metastatic effects of certain antitumor
drugs individually, and in combination with radiation on orthotopic
xenografts of metastatic sublines will be characterized and quantitated to
develop improved treatment protocols. The isolation of tumor cell
subpopulations from primary tumor and the characterization of factors
responsible for invasive and metastatic behavior might suggest new and
improved clinical treatment strategies for controlling the malignant
progression of prostatic carcinoma.
StatusFinished
Effective start/end date4/1/947/31/09

Funding

  • National Institutes of Health: $201,317.00
  • National Institutes of Health
  • National Institutes of Health: $265,125.00
  • National Institutes of Health: $99,450.00
  • National Institutes of Health
  • National Institutes of Health: $205,197.00
  • National Institutes of Health
  • National Institutes of Health: $265,125.00
  • National Institutes of Health: $101,878.00
  • National Institutes of Health: $209,672.00
  • National Institutes of Health: $258,895.00
  • National Institutes of Health: $99,450.00
  • National Institutes of Health: $265,125.00

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Prostatic Neoplasms
Neoplasms
Pharmaceutical Preparations
Cytokines
Neoplasm Metastasis
Drug Resistance
Basement Membrane
Therapeutics
Anti-Inflammatory Agents
Doxorubicin
Carcinoma
Interleukin-8
Drug Therapy
Heterografts
Interleukin-6
Multiple Drug Resistance
Stromal Cells
Complementary DNA
Paclitaxel
Celecoxib

ASJC

  • Medicine(all)