In spite of many complex and aggressive
approaches to therapy and great strides in understanding the biology
and etiology of lung cancer, corresponding improvements in outcome
are not yet apparent. It is hoped that in the future, advances in our
knowledge of the molecular biology of lung cancer will provide the
foundation for real improvement in outcomes. Emerging molecularly
based modalities that may soon be combined with chemotherapy,
radiation therapy, and surgery to improve the effectiveness of lung
cancer treatment are discussed.
It is quite clear that lung cancer is caused by an accumulation of
genetic damage in the bronchial epithelium. Exposure to inhaled
carcinogens, such as the polycyclic aromatic hydrocarbons and the
nitrosamines from cigarette smoke, can directly damage the DNA of
bronchial epithelial cells. These agents covalently modify DNA,
causing misreplication and mutation or loss of genetic material. The
bound carcinogens can be directly detected in the DNA of smokers,
and, disturbingly, also in the DNA of infants born to smoking
mothers. Using modern molecular detection techniques, loss of
genetic material from large regions of chromosomes or point mutations
in dominant or recessive oncogenes can be found in the bronchial
epithelium of smokers, even those without microscopically visible
histological changes. Prolonged exposure results in visible
hyperplasia and metaplasia, which often, but not always, precede
frank malignancy. It is likely that detectable genetic abnormalities
always precede the development of invasive cancer. New molecular
markers of loss of growth control, such as loss of expression of the
retinoic acid receptor beta (RAR-b), have
been found to be strongly associated with malignant progression and
are being tested as molecular intermediate markers in chemoprevention
and early detection studies. These genetic premalignant changes are
widespread throughout the respiratory epithelium, suggesting that a
field effect is induced by the carcinogens, explaining the high
incidence of second malignancies in those cured of lung cancer or
head and neck cancer.
It is clinically useful to categorize bronchogenic cancers into two
groups that reflect their biology and management: small-cell lung
cancer and nonsmall-cell lung cancer. Small-cell lung cancer is
highly responsive to chemotherapy, but only very infrequently
curable, as it rapidly relapses and metastasizes. Nonsmall-cell
lung cancer is often less dramatically responsive to chemotherapy,
but is more often cured by surgery or combined-modality therapy. Each
of these categories is divided into subtypes, but as mentioned above,
in reality, these categories often blend into each other or coexist
with each other. Data on cellular and molecular biology, as well as
ultrastructural studies, can help refine these groupings, and more
importantly, perhaps guide therapy in the future.
Small-cell lung cancer tumors and a subset of nonsmall-cell
lung cancer tumors express many neuroendocrine markers.
Neuroendocrine cells are present in small numbers in many tissues and
share many properties with neural cells, hence the term. The primary
function of these neuroendocrine cells is to produce, package, and
secrete small peptide or amine hormones. Lung tumors, especially
small-cell lung cancer, may secrete factors that stimulate their own
growth (autocrine secretion). Individual tumors may secrete up to 10
discrete hormones, which may contribute to the paraneoplastic
syndromes often associated with small-cell lung cancer.
Cross-reactive antigens, such as the HuD gene, may also lead to
autoimmune paraneoplastic syndromes.
Small-cell lung cancer is strongly associated with cigarette smoking,
and nearly always demonstrates loss of genetic material on
chromosomes, including the gene for RAR-b
and FHIT (fragile histidine triad), but the important genes are not
fully identified. Mutations in the ras oncogene are rare, but
mutations in p53 and overexpression of bcl-2 are nearly universal.
These abnormalities form the basis for several new therapeutic
approaches. One of these is the inhibition of expression of bcl-2 in
small-cell lung cancer using antisense oligonucleotides or other
approaches. The antisense oligonucleotides have been found to be
highly effective in cell lines, and if nontoxic methods can be
developed to inhibit bcl-2 expression in patients, this will be a
promising new modality.
Nonsmall-cell lung cancer is a morphologically diverse group
that includes the squamous (epidermoid) carcinoma, adenocarcinoma,
and large-cell carcinoma. The squamous phenotype used to be the
predominant form of lung cancer worldwide, although its relative and
absolute incidence in the United States (and other parts of the world
such as East Asia) has dramatically declined within the last two
decades. Squamous carcinomas are strongly associated with
cigarette smoking, and this explains their frequent association with
metaplastic and dysplastic changes in adjacent epithelium.
Adenocarcinomas have become the most common form of lung cancer in
the United States. In general, they tend to arise in the peripheral
airways and may possess distinctive intracellular mucin granules as
part of their acinar/glandular differentiation.
Mutations in p53 are observed in about half of nonsmall-cell
lung cancers, occurring somewhat more frequently in squamous cell
carcinomas, whereas ras mutations are found in about 20% of
adenocarcinomas and less frequently in squamous carcinomas.
Several approaches are being clinically tested that are based on the
tumor-suppressive properties of p53. One of these is the delivery of
a normal p53 in a recombinant adenovirus to cause high-level
expression of this tumor-suppressor gene. Overexpression of p53 has
been found to be selectively toxic to tumor cells and not normal
ones. The normal p53 is delivered by direct injection into tumor
masses either alone or in combination with radiation or
chemotherapy. It is hoped that this combination will allow
improved local control and palliation of unresectable tumors. An
Eastern Cooperative Oncology Group study is evaluating adenovirus-p53
delivered by bronchoalveolar lavage directly to entire lobes of the
lung with bronchoalveolar carcinoma. This approach should allow
excellent access of the gene therapeutic vector to the tumor cells
that cause the main respiratory symptoms of this disease; that is,
those lining and involving the alveoli and small airways.
Overexpression of several growth factor receptors, such as
insulin-like growth factor 1 receptor (IGF-1r) and epidermal growth
factor receptor (EGFr), as well as HER-2/neu, has also been observed
and may be correlated with the biology of lung cancer, and, thus,
important therapeutic targets. Several companies are developing
small-molecule antagonists of tyrosine kinase receptors, such as EGFr
and IGF-1r, for clinical application. Gene-based therapeutic
approaches to block these receptors have been effective in animal
models. Similarly, antibodies against HER-2/neu, found to be
useful in breast cancer, are now being tested in nonsmall-cell
1. Everson RB, Randerath E, Santella RM, et al: Quantitative
associations between DNA damage in human placenta and maternal
smoking and birth weight. J Natl Cancer Inst 80:567-576, 1988.
2. Wistuba II, Lam S, Behrens C, et al: Molecular damage in the
bronchial epithelium of current and former smokers. J Natl Cancer
Inst 89:1366-1373, 1997.
3. Franklin WA, Gazdar AF, Haney J, et al: Widely dispersed p53
mutation in respiratory epithelium: A novel mechanism for field
carcinogenesis. J Clin Invest 100:2133-2137, 1997.
4. Ziegler A, Luedke GH, Fabbro D, et al: Induction of apoptosis in
small-cell lung cancer cells by an antisense oligodeoxynucleotide
targeting the Bcl-2 coding sequence. J Natl Cancer Inst 89:1027-1036, 1997.
5. Gazdar AF, Carbone DP: The Biology and Molecular Genetics of Lung
Cancer. Austin, Tex, R.G. Landes, 1994.
6. Chiba I, Takahashi T, Nau MM, et al: Mutations in the p53 gene are
frequent in primary, resected nonsmall-cell lung cancer.
Oncogene 5:1603-1610, 1990.
7. Mitsudomi T, Steinberg SM, Oie HK, et al: ras gene mutations in
nonsmall-cell lung cancers are associated with shortened
survival irrespective of treatment intent. Cancer Res 51:4999-5002, 1991.
8. Roth JA, Swisher SG, Merritt JA, et al: Gene therapy for
nonsmall-cell lung cancer: A preliminary report of a phase I
trial of adenoviral p53 gene replacement. Semin Oncol 25(3 suppl
9. Lee CT, Wu S, Gabrilovich D, et al: Antitumor effects of an
adenovirus expressing antisense insulin-like growth factor I receptor
on human lung cancer cell lines. Cancer Res 56:3038-3041, 1996.
10. Folkman J: Angiogenesis in cancer, vascular, rheumatoid, and
other disease. Nat Med l:27-31, 1995.
11. De Plaen E, Lurquin C, Van Pel A, et al: Immunogenic (tum-)
variants of mouse tumor P815: Cloning of the gene of tum-antigen P91A
and identification of the tum-mutation. Proc Natl Acad Sci USA
12. Lurquin C, Van Pel A, Mariamé B, et al: Structure of the
gene of tum-transplantation antigen P91A: The mutated exon encodes a
peptide recognized with Ld by cytolytic T cells. Cell 58:293-303, 1989.
13. Kawakami Y, Eliyahu S, Jennings C, et al: Recognition of multiple
epitopes in the human melanoma antigen gp 100 by tumor-infiltrating T
lymphocytes associated with in vivo tumor regression. J Immunol
14. Cole DJ, Weil DP, Shilyansky J, et al: Characterization of the
functional specificity of a cloned T-cell receptor heterodimer
recognizing the MART-1 melanoma antigen. Cancer Res 55:748-752, 1995.
15. Wang RF, Robbins PF, Kawakami Y, et al: Identification of a gene
encoding a melanoma tumor antigen recognized by HLA-A31-restricted
tumor-infiltrating lymphocytes. [Published erratum appears in J Exp
Med 181(3):1261, 1995.] J Exp Med 181:799-804, 1995.
16. Topalian SL, Rivoltini L, Mancini M, et al: Human CD4+ T cells
specifically recognize a shared melanoma-associated antigen encoded
by the tyrosinase gene. Proc Natl Acad Sci USA 91:9461-9465, 1994.
17. Salgaller ML, Weber JS, Koenig S, et al: Generation of specific
anti-melanoma reactivity by stimulation of human tumor-infiltrating
lymphocytes with MAGE-1 synthetic peptide. Cancer Immunol Immunother
18. Kawakami Y, Eliyahu S, Sakaguchi K, et al: Identification of the
immunodominant peptides of the MART-1 human melanoma antigen
recognized by the majority of HLA-A2-restricted tumor infiltrating
lymphocytes. J Exp Med 180:347-352, 1994.
19. Ciernik IF, Berzofsky JA, Carbone DP: Induction of cytotoxic T
lymphocytes and antitumor immunity with DNA vaccines expressing
single T cell epitopes. J Immunol 156:2369-2375, 1996.
20. Speiser DE, Miranda R, Zakarian A, et al: Self antigens expressed
by solid tumors do not efficiently stimulate naive or activated T
cells: Implications for immunotherapy. J Exp Med 186:645-653, 1997.
21. Eilber FR, Morton DL: Impaired immunologic reactivity and
recurrence following cancer surgery. Cancer 25:362-367, 1970.
22. Hughes LE, MacKay WD: Suppression of the tuberculin response in
malignant disease. Br Med J 5474:1346-1348, 1965.
23. Solowey AC, Rapaport FT: Immunologic responses in cancer
patients. Surg Gynecol Obstet 121:756-760, 1965.
24. Stiver HG, Weinerman BH: Impaired serum antibody response to
inactivated influenza A and B vaccine in cancer patients. Can Med
Assoc J 119:733-738, 1978.
25. Ioannides CG, Whiteside TL: T cell recognition of human tumors:
Implications for molecular immunotherapy of cancer. Clin Immunol
Immunopathol 66:91-106, 1993.
26. Rock KL, Rothstein L, Gamble S, et al: Characterization of
antigen-presenting cells that present exogenous antigens in
association with class I MHC molecules. J Immunol 150:438-446, 1993.
27. Huang AY, Golumbek P, Ahmadzadeh M, et al: Role of bone
marrow-derived cells in presenting MHC class I-restricted tumor
antigens. Science 264:961-965, 1994.
28. Steinman RM: The dendritic cell system and its role in
immunogenicity. Annu Rev Immunol 9:271-296, 1991.
29. Grabbe S, Bruvers S, Gallo RL, et al: Tumor antigen presentation
by murine epidermal cells. J Immunol 146:3656-3661, 1991.
30. Cohen PJ, Cohen PA, Rosenberg SA, et al: Murine epidermal
Langerhans cells and splenic dendritic cells present tumor-associated
antigens to primed T cells. Eur J Immunol 24:315-319, 1994.
31. Takahashi H, Nakagawa Y, Yokomuro K, et al: Induction of CD8+
cytotoxic T lymphocytes by immunization with syngeneic irradiated
HIV-1 envelope-derived, peptide-pulsed dendritic cells. Int Immunol
32. Nonacs R, Humborg C, Tam JP, et al: Mechanisms of mouse spleen
dendritic cell function in the generation of influenza-specific,
cytolytic T lymphocytes. J Exp Med 176:519-529, 1992.
33. Gabrilovich DI, Nadaf S, Corak J, et al: Dendritic cells in
antitumor immune responses. II. Dendritic cells grown from bone
marrow precursors, but not mature DC from tumor-bearing mice, are
effective antigen carriers in the therapy of established tumors. Cell
Immunol 170:111-119, 1996.
34. Zitvogel L, Mayordomo JI, Tjandrawan T, et al: Therapy of murine
tumors with tumor peptide-pulsed dendritic cells: Dependence on T
cells, B7 costimulation, and T helper cell 1-associated cytokines. J
Exp Med 183:87-97, 1996.
35. Tas, MP, Simons PJ, Balm FJ, et al: Depressed monocyte
polarization and clustering of dendritic cells in patients with head
and neck cancer: In vitro restoration of this immuosuppression by
thymic hormones. Cancer Immunol Immunother 36:108-114, 1993.
36. Thurnher M, Radmayr C, Ramoner R, et al: Human renal-cell
carcinoma tissue contains dendritic cells. Int J Cancer 68:1-7, 1996.
37. Chaux P, Moutet M, Faivre J, et al: Inflammatory cells
infiltrating human colorectal carcinomas express HLA class II but not
B7-1 and B7-2 costimulatory molecules of the T-cell activation. Lab
Invest 74:975-983, 1996.
38. Nestle FO, Burg G, Fah J, et al: Human sunlight-induced
basal-cell-carcinoma-associated dendritic cells are deficient in T
cell costimulatory molecules and are impaired as antigen-presenting
cells. Am J Pathol 150:641-651, 1997.
39. Gabrilovich DI, Ciernik IF, Carbone DP: Dendritic cells in
antitumor immune responses. I. Defective antigen presentation in
tumor-bearing hosts. Cell Immunol 170:101-110, 1996.
40. Kerrebijn JD, Simons PJ, Tas M, et al: In vivo effects of
thymostimulin treatment on monocyte polarization, dendritic cell
clustering and serum p15E-like transmembrane factors in operable head
and neck squamous cell carcinoma patients. Eur Arch Otorhinolaryngol
41. Buelens C, Willems F, Delvaux A, et al: Interleukin-10
differentially regulates B7-1 (CD80) and B7-2 (CD86) expression on
human peripheral blood dendritic cells. Eur J Immunol 25:2668-2672, 1995.
42. Gabrilovich DI, Cunningham HT, Carbone DP: IL-12 and mutant p53
peptide-pulsed dendritic cells for the specific immunotherapy of
cancer. J Immunother 19:414-418, 1997.
43. Gabrilovich DI, Corak J, Ciernik IF, et al: Decreased antigen
presentation by dendritic cells in patients with breast cancer. Clin
Cancer Res 3:483-490, 1997.
44. Gabrilovich DI, Chen HL, Girgis KR, et al: Production of vascular
endothelial growth factor by human tumors inhibits the functional
maturation of dendritic cells. Nat Med 2:1096-1103, 1996.
45. Oyama T, Ran S, Ishida T, et al: Vascular endothelial growth
factor affects dendritic cell maturation through the inhibition of
nuclear factor-kappa B activation in hemopoietic progenitor cells. J
Immunol 160:1224-1232, 1998.